|
1
|
Shweikeh F, Torres Y, Khan K, Mouchli M, Singh I. Hepatitis C associated mixed cryoglobulinemia glomerulonephritis in the setting of undetectable viral load: successful treatment with hydroxychloroquine and review of the literature. Immunol Res 2025; 73:55. [PMID: 39979644 DOI: 10.1007/s12026-025-09608-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 02/14/2025] [Indexed: 02/22/2025]
Abstract
There are an estimated 58 million cases of Hepatitis C (HCV) worldwide. Approximately 38-76% of individuals can develop extrahepatic manifestations such as mixed cryoglobulinemia (MC). Importantly, the appearance of symptoms due to MC is linked by detectable HCV RNA. A 38-year-old male with remote history of HCV infection diagnosed 8 years prior presented to the emergency department with subacute renal failure with proteinuria, hematuria, and WBC/RBC casts. Biopsy confirmed acute proliferative, non-crescentic, inflammatory glomerulonephritis. He also had new onset cryoglobulinemia. His HCV RNA was low-grade and liver function tests were all within the normal range. A liver biopsy showed signs of chronic hepatitis with mildly active portal fibrosis. The MC was cleared with steroids and a re-measured HCV RNA quantitative was negative. Seven months later, he was readmitted with glomerulonephritis and elevated MC. However, the patient's HCV viral load was undetectable. The patient underwent 6 rounds of plasmapheresis and 6 doses of Rituximab were given with suppression of cryoglobulin to nil. A month later, the MC levels rose again, while the viral load remained undetectable with the possibility of spontaneous remission. After initiation of maintenance hydroxychloroquine, his GFR improved to normal over the next 2 years. Multiple theories have been suggested for the phenomenon including presence of residual virus and lymphoproliferation effects. Hydroxychloroquine could be a successful option, though future studies should corroborate our outcome.
Collapse
Affiliation(s)
- Faris Shweikeh
- Department of Internal Medicine, Cleveland Clinic Akron General, Akron, OH, USA.
| | - Yaritza Torres
- College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Khadeja Khan
- Department of Internal Medicine, Mount Carmel Grove City Hospital, Columbus, OH, USA
| | - Mohamad Mouchli
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Inderprit Singh
- Department of Rheumatologic and Immunologic Disease, Cleveland Clinic Akron General, Akron, OH, USA
| |
Collapse
|
|
2
|
Echevarria-Lima J, Moles R. Monocyte and Macrophage Functions in Oncogenic Viral Infections. Viruses 2024; 16:1612. [PMID: 39459945 PMCID: PMC11512331 DOI: 10.3390/v16101612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 10/07/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
Monocytes and macrophages are part of innate immunity and constitute the first line of defense against pathogens. Bone marrow-derived monocytes circulate in the bloodstream for one to three days and then typically migrate into tissues, where they differentiate into macrophages. Circulatory monocytes represent 5% of the nucleated cells in normal adult blood. Following differentiation, macrophages are distributed into various tissues and organs to take residence and maintain body homeostasis. Emerging evidence has highlighted the critical role of monocytes/macrophages in oncogenic viral infections, mainly their crucial functions in viral persistence and disease progression. These findings open opportunities to target innate immunity in the context of oncogenic viruses and to explore their potential as immunotherapies.
Collapse
Affiliation(s)
- Juliana Echevarria-Lima
- Laboratório de Imunologia Básica e Aplicada, Department of Immunology, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil;
| | - Ramona Moles
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS 39216, USA
- Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA
- Center for Immunology and Microbial Research, University of Mississippi Medical Center, Jackson, MS 39216, USA
| |
Collapse
|
|
3
|
Rossetto A, Adani GL, Baccarani U, Tulissi P, Bresadola V. Pathological Consequences in Anti-HCV Antibody-Positive Organ Donation to an Anti-HCV Antibody-Negative Recipient. Transplant Proc 2024; 56:1213-1215. [PMID: 39034192 DOI: 10.1016/j.transproceed.2024.02.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/05/2024] [Accepted: 02/15/2024] [Indexed: 07/23/2024]
Abstract
BACKGROUND The need to expand the pool of available organs for transplantation has meant that the use of marginal organs is increasingly widespread. The advent of antiviral therapy for hepatitis C virus (HCV) has made it possible to consider the donation of organs from HCV-positive donors and even from viremic donors. METHODS In HCV-positive to HCV-negative antibody donor transplantation, the development of antibodies to HCV is uneven, depending on the organ transplanted and with differences in the time of appearance. Whether the subsequent disappearance is attributed to the development of antibodies or the transmission of immunity between donor and recipient remains unclear. In transplantation from an HCV-infected donor to a HCV-seronegative recipient, the administration of antiviral therapy to the recipient before transplantation or a few days after transplantation achieves sustained response in almost all cases. We wanted to deepen the argument by studying the data in the literature, focusing on kidney transplantation, considering that this could be of interest, particularly for possible long-term renal damage. RESULTS HCV infection both ongoing and previous, as well as the presence of HCV antibodies alone, can be responsible for kidney damage. CONCLUSIONS Direct-acting anti-HCV therapy has revolutionized the treatment of HCV disease and the therapeutic possibilities of transplantation. However, we believe it is useful to keep in mind the pathophysiology of HCV-related damage especially in patients with a long life expectancy, using all emerging strategies to minimize the risk of transmission of infection or development of viremia.
Collapse
Affiliation(s)
- Anna Rossetto
- General Surgery Unit, Area Medical Department, University of Udine, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy.
| | - Gian Luigi Adani
- General Surgery and Kidney Transplantation, Siena University Hospital, Siena, Italy
| | - Umberto Baccarani
- General Surgery and Transplantation, Area Medica Department, University of Udine, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
| | - Patrizia Tulissi
- Department of Nephrology, Dialysis, and Kidney Transplantation, Azienda Sanitaria Universitaria Friuli Centrale Udine, Italy
| | - Vittorio Bresadola
- General Surgery Unit, Area Medical Department, University of Udine, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
| |
Collapse
|
|
4
|
Wang J, Dai D, Wen Y. Repeated Hepatitis C Virus Recurrence in a Patient With a Prognosis of Ultimate Spontaneous Clearance: Relapse or Reinfection? Am J Ther 2023; 30:e470-e473. [PMID: 37713699 DOI: 10.1097/mjt.0000000000001602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Affiliation(s)
| | - Di Dai
- Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Ying Wen
- Departments of Infectious Diseases
| |
Collapse
|
|
5
|
Mahmoud Farhan S, Mahmoud Abd El-Baky R, Mohammad Abdalla SA, Osama El-Gendy A, Farag Azmy A. Efficacy of Amikacin and Imipenem Against Multi-Drug Resistant Gram-Negative Bacteria Isolated from Wound Infections, Egypt. IRANIAN JOURNAL OF MEDICAL MICROBIOLOGY 2023; 17:218-229. [DOI: 10.30699/ijmm.17.2.218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
|
|
6
|
Su CM, Du Y, Rowland RRR, Wang Q, Yoo D. Reprogramming viral immune evasion for a rational design of next-generation vaccines for RNA viruses. Front Immunol 2023; 14:1172000. [PMID: 37138878 PMCID: PMC10149994 DOI: 10.3389/fimmu.2023.1172000] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 04/03/2023] [Indexed: 05/05/2023] Open
Abstract
Type I interferons (IFNs-α/β) are antiviral cytokines that constitute the innate immunity of hosts to fight against viral infections. Recent studies, however, have revealed the pleiotropic functions of IFNs, in addition to their antiviral activities, for the priming of activation and maturation of adaptive immunity. In turn, many viruses have developed various strategies to counteract the IFN response and to evade the host immune system for their benefits. The inefficient innate immunity and delayed adaptive response fail to clear of invading viruses and negatively affect the efficacy of vaccines. A better understanding of evasion strategies will provide opportunities to revert the viral IFN antagonism. Furthermore, IFN antagonism-deficient viruses can be generated by reverse genetics technology. Such viruses can potentially serve as next-generation vaccines that can induce effective and broad-spectrum responses for both innate and adaptive immunities for various pathogens. This review describes the recent advances in developing IFN antagonism-deficient viruses, their immune evasion and attenuated phenotypes in natural host animal species, and future potential as veterinary vaccines.
Collapse
Affiliation(s)
- Chia-Ming Su
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Yijun Du
- Shandong Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, Shandong, China
| | - Raymond R. R. Rowland
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Qiuhong Wang
- Center for Food Animal Health, Department of Animal Sciences, College of Food, Agricultural, and Environmental Sciences, The Ohio State University, Wooster, OH, United States
- Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University, Columbus, OH, United States
| | - Dongwan Yoo
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, United States
- *Correspondence: Dongwan Yoo,
| |
Collapse
|
|
7
|
Mbaga DS, Kenmoe S, Njiki Bikoï J, Takuissu GR, Amougou-Atsama M, Atenguena Okobalemba E, Ebogo-Belobo JT, Bowo-Ngandji A, Oyono MG, Magoudjou-Pekam JN, Kame-Ngasse GI, Nka AD, Feudjio AF, Zemnou-Tepap C, Adamou Velhima E, Ndzie Ondigui JL, Nayang-Mundo RA, Touangnou-Chamda SA, Kamtchueng Takeu Y, Taya-Fokou JB, Mbongue Mikangue CA, Kenfack-Momo R, Kengne-Ndé C, Sake CS, Esemu SN, Njouom R, Ndip L, Riwom Essama SH. Global prevalence of occult hepatitis C virus: A systematic review and meta-analysis. World J Methodol 2022; 12:179-190. [PMID: 35721241 PMCID: PMC9157636 DOI: 10.5662/wjm.v12.i3.179] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/03/2022] [Accepted: 04/29/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Occult hepatitis C infection (OCI) is characterized by the presence of hepatitis C virus (HCV) RNA in the liver, peripheral blood mononuclear cells (PBMC) and/or ultracentrifuged serum in the absence of detectable HCV-RNA in serum. OCI has been described in several categories of populations including hemodialysis patients, patients with a sustained virological response, immunocompromised individuals, patients with abnormal hepatic function, and apparently healthy subjects. AIM To highlight the global prevalence of OCI. METHODS We performed a systematic and comprehensive literature search in the following 4 electronic databases PubMed, EMBASE, Global Index Medicus, and Web of Science up to 6th May 2021 to retrieve relevant studies published in the field. Included studies were unrestricted population categories with known RNA status in serum, PBMC, liver tissue and/or ultracentrifuged serum. Data were extracted independently by each author and the Hoy et al tool was used to assess the quality of the included studies. We used the random-effect meta-analysis model to estimate the proportions of OCI and their 95% confidence intervals (95%CI). The Cochran's Q-test and the I 2 test statistics were used to assess heterogeneity between studies. Funnel plot and Egger test were used to examine publication bias. R software version 4.1.0 was used for all analyses. RESULTS The electronic search resulted in 3950 articles. We obtained 102 prevalence data from 85 included studies. The pooled prevalence of seronegative OCI was estimated to be 9.61% (95%CI: 6.84-12.73) with substantial heterogeneity [I² = 94.7% (95%CI: 93.8%-95.4%), P < 0.0001]. Seropositive OCI prevalence was estimated to be 13.39% (95%CI: 7.85-19.99) with substantial heterogeneity [I 2 = 93.0% (90.8%-94.7%)]. Higher seronegative OCI prevalence was found in Southern Europe and Northern Africa, and in patients with abnormal liver function, hematological disorders, and kidney diseases. Higher seropositive OCI prevalence was found in Southern Europe, Northern America, and Northern Africa. CONCLUSION In conclusion, in the present study, it appears that the burden of OCI is high and variable across the different regions and population categories. Further studies on OCI are needed to assess the transmissibility, clinical significance, long-term outcome, and need for treatment.
Collapse
Affiliation(s)
- Donatien Serge Mbaga
- Department of Microbiology, The University of Yaounde I, Yaounde 00237, Cameroon
| | - Sebastien Kenmoe
- Department of Microbiology and Parasitology, University of Buea, Buea 00237, Cameroon
- Department of Virology, Centre Pasteur of Cameroon, Yaounde 00237, Cameroon
| | - Jacky Njiki Bikoï
- Department of Microbiology, The University of Yaounde I, Yaounde 00237, Cameroon
| | - Guy Roussel Takuissu
- Centre of Research in Food, Food Security and Nutrition, Institute of Medical Research and Medicinal Plants Studies, Yaounde 00237, Cameroon
| | - Marie Amougou-Atsama
- Centre de Recherche sur les Maladies Emergentes et Re-Emergentes, Institute of Medical Research and Medicinal Plants Studies, Yaounde 00237, Cameroon
| | | | - Jean Thierry Ebogo-Belobo
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaounde 00237, Cameroon
| | - Arnol Bowo-Ngandji
- Department of Microbiology, The University of Yaounde I, Yaounde 00237, Cameroon
| | - Martin Gael Oyono
- Laboratory of Parasitology and Ecology, The University of Yaounde I, Yaounde 00237, Cameroon
| | | | - Ginette Irma Kame-Ngasse
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaounde 00237, Cameroon
| | - Alex Durand Nka
- Virology Laboratory, Chantal Biya International Reference Center for Research on HIV/AIDS Prevention and Management, Yaounde 00237, Cameroon
| | | | - Cromwel Zemnou-Tepap
- Department of Biochemistry, The University of Yaounde I, Yaounde 00237, Cameroon
| | - Elie Adamou Velhima
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaounde 00237, Cameroon
| | | | | | | | - Yrene Kamtchueng Takeu
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaounde 00237, Cameroon
| | | | | | - Raoul Kenfack-Momo
- Department of Biochemistry, The University of Yaounde I, Yaounde 00237, Cameroon
| | - Cyprien Kengne-Ndé
- Epidemiological Surveillance, Evaluation and Research Unit, National Aids Control Committee, Douala 00237, Cameroon
| | | | - Seraphine Nkie Esemu
- Department of Microbiology and Parasitology, University of Buea, Buea 00237, Cameroon
| | - Richard Njouom
- Department of Virology, Centre Pasteur of Cameroon, Yaounde 00237, Cameroon
| | - Lucy Ndip
- Department of Microbiology and Parasitology, University of Buea, Buea 00237, Cameroon
| | | |
Collapse
|
|
8
|
Ismail B, Benrajab KM, Bejarano P, Ruiz P, Sears D, Tzakis A, Zervos XB. Benign course of residual inflammation at end of treatment of liver transplant recipients after sofosbuvir based therapy. World J Hepatol 2022; 14:602-611. [PMID: 35582292 PMCID: PMC9055203 DOI: 10.4254/wjh.v14.i3.602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 12/16/2021] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Persistent inflammation on histology after successful hepatitis C (HCV) treatment has been reported. However, data regarding the long-term impact in liver transplant recipients is limited, particularly after using direct-acting antiviral (DAA) therapies.
AIM To evaluate the impact of successful treatment with DAAs on histological changes and occult HCV and to describe the clinical course of residual inflammation in liver transplant recipients.
METHODS We conducted a case series of 13 chronic HCV infected liver transplant recipients successfully treated with DAAs between December 2013 and May 2014. All patients were treated for 24 wk and had non-detectable serum HCV RNA by the time of biopsy. Only patients with at least one liver biopsy at or after treatment were included. We examined liver biopsies for evidence of residual inflammation and the presence of intrahepatic HCV RNA.
RESULTS Persistent inflammation was seen in 12/13 patients on end of treatment biopsy. Inflammation was still seen in the available five follow-up biopsies (range 38-48 wk after the end of treatment). Intrahepatic HCV RNA was undetectable in all biopsies. All patients had preserved graft function for a mean follow-up of 2.5 years, except one that developed chronic rejection.
CONCLUSION After successful HCV treatment with DAAs, liver transplant recipients may have persistent inflammation on biopsy without evidence of intracellular RNA. The clinical outcome remained favorable in most patients. Further studies with a larger number and longer follow-up are needed to establish the implication of this finding on long-term graft function.
Collapse
Affiliation(s)
- Bahaaeldeen Ismail
- Division of Digestive Diseases and Nutrition, University of Kentucky College of Medicine, Lexington, KY 40536, United States
| | - Karim M Benrajab
- Division of Digestive Diseases and Nutrition, University of Kentucky College of Medicine, Lexington, KY 40536, United States
| | - Pablo Bejarano
- Department of Pathology, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Phillip Ruiz
- Department of Pathology, University of Miami Miller School of Medicine, Miami, FL 33136, United States
| | - Debbie Sears
- Department of Liver Transplant, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Andreas Tzakis
- Department of Liver Transplant, Cleveland Clinic Florida, Weston, FL 33331, United States
| | | |
Collapse
|
|
9
|
Desombere I, Van Houtte F, Farhoudi A, Verhoye L, Buysschaert C, Gijbels Y, Couvent S, Swinnen W, Van Vlierberghe H, Elewaut A, Magri A, Stamataki Z, Meuleman P, McKeating JA, Leroux-Roels G. A Role for B Cells to Transmit Hepatitis C Virus Infection. Front Immunol 2021; 12:775098. [PMID: 34975862 PMCID: PMC8716873 DOI: 10.3389/fimmu.2021.775098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 11/29/2021] [Indexed: 12/02/2022] Open
Abstract
Hepatitis C virus (HCV) is highly variable and transmits through infected blood to establish a chronic liver infection in the majority of patients. Our knowledge on the infectivity of clinical HCV strains is hampered by the lack of in vitro cell culture systems that support efficient viral replication. We and others have reported that HCV can associate with and infect immune cells and may thereby evade host immune surveillance and elimination. To evaluate whether B cells play a role in HCV transmission, we assessed the ability of B cells and sera from recent (<2 years) or chronic (≥ 2 years) HCV patients to infect humanized liver chimeric mice. HCV was transmitted by B cells from chronic infected patients whereas the sera were non-infectious. In contrast, B cells from recently infected patients failed to transmit HCV to the mice, whereas all serum samples were infectious. We observed an association between circulating anti-glycoprotein E1E2 antibodies and B cell HCV transmission. Taken together, our studies provide evidence for HCV transmission by B cells, findings that have clinical implications for prophylactic and therapeutic antibody-based vaccine design.
Collapse
Affiliation(s)
| | - Freya Van Houtte
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Ali Farhoudi
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Lieven Verhoye
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | | | - Yvonne Gijbels
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Sibyl Couvent
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | | | - Hans Van Vlierberghe
- Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium
- Laboratory of Hepatology Research, Ghent University, Ghent, Belgium
| | - André Elewaut
- Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium
- Laboratory of Hepatology Research, Ghent University, Ghent, Belgium
| | - Andrea Magri
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Zania Stamataki
- Institute of Immunology and Immunotherapy, Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, United Kingdom
- National Institute for Health Researc (NIHR) Birmingham Liver Biomedical Research Centre, University Hospitals Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
| | - Philip Meuleman
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Jane A McKeating
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | | |
Collapse
|
|
10
|
Occult Infection with Hepatitis C Virus: Looking for Clear-Cut Boundaries and Methodological Consensus. J Clin Med 2021; 10:jcm10245874. [PMID: 34945170 PMCID: PMC8707082 DOI: 10.3390/jcm10245874] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/11/2021] [Accepted: 12/13/2021] [Indexed: 02/07/2023] Open
Abstract
The sustained virologic response and elimination of HCV is widely viewed as a true cure of chronic hepatitis C as it associates with amelioration of histological liver damage and improved clinical outcomes. Therefore, the existence and clinical burden of occult HCV infection (OCI) has been a controversial issue for many years. In this review, we summarize recently published data that adds new information on the molecular and clinical background of OCI and its epidemiological significance. We also identify and discuss the most important methodological pitfalls, which can be a source of inconsistency between studies. Data that have accumulated so far, strongly support the existence of extrahepatic HCV replication in individuals negative for serum HCV-RNA by conventional clinical tests. OCI emerges as a condition where the immune system is unable to fully resolve infection but it is continuously stimulated by low levels of HCV antigens, leading to progression of liver pathology and extrahepatic HCV-related complications. Moreover, the development of monitoring strategies or management guidelines for OCI is still hampered by the lack of clear definition and the confusion regarding its clinical significance. Careful study design and the introduction of uniform protocols for the detection of low-level HCV-RNA are crucial for obtaining reliable data on OCI.
Collapse
|
|
11
|
Serwah MA, Omar SA, Khedr MS, Abdel-Hamid AES. Occurrence and clinical characteristics of occult hepatitis C virus infection in hemodialysis units at Ismailia, Egypt. Eur J Gastroenterol Hepatol 2021; 33:1009-1014. [PMID: 33731578 DOI: 10.1097/meg.0000000000002075] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND AND AIMS Occult hepatitis C infection is defined as the presence of hepatitis C virus RNA in peripheral blood mononuclear cells (PBMC) ± hepatocytes in the absence of HCV-RNA in serum. It has been a lot of debate and controversy in recent years and not discussed well. This issue has not been discussed or investigated in Egypt, especially in patients on hemodialysis in Ismailia. This study is the first one to investigate the prevalence of occult HCV infection in large populations of chronic hemodialysis (CHD) patients in Ismailia, Egypt. METHODS Our study is cross-sectional analytic and included 204 CHD patients; who are negative for HCV infection. Sensitive commercial real-time assay was used to detect HCV-RNA in PBMC. In our study, the presence of genomic HCV-RNA in PBMCs of all these patients was detected by real-time PCR. On the other hand, 22 patients on hemodialysis with an established diagnosis of chronic hepatitis C virus infection were included as a control group and examined by real-time PCR was used to evaluate HCV infection. RESULTS Occult HCV infection is defined as the presence of HCV-RNA in PBMNCs in patients on chronic hemodialysis, and it was found in 14/204 (7%) of the patients. Patients who were on CHD for a longer time are susceptible to occult HCV infection, and their mean alanine aminotransferase levels are significantly higher during the last 3 months before study entry. In comparison, chronic HCV patients have elevated bilirubin, aspartate transferase and alanine transferase than occult HCV infection. CONCLUSIONS The prevalence of occult HCV infection was 7% in our CHD patients. No available data are showing the virulence of this form of virus. However, further studies in other geographic populations with high HCV endemicity are needed to clarify the significance of occult HCV infection in these patient groups, in addition to test for the presence of negative antigenomic strand to confirm or disconfirm the reliability of occult HCV.
Collapse
Affiliation(s)
| | - Seham A Omar
- Internal Medicine Department, Faculty of Medicine and Clinical Pathology Department
| | - Mohamed S Khedr
- Internal Medicine Department, Faculty of Medicine and Clinical Pathology Department
| | | |
Collapse
|
|
12
|
Miyashita K, Hongo Y, Nakashima A, Kato S, Kusano H, Morizono S, Higashi N. Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy. Intern Med 2021; 60:1533-1539. [PMID: 33191319 PMCID: PMC8188017 DOI: 10.2169/internalmedicine.4768-20] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
Collapse
Affiliation(s)
- Kaname Miyashita
- Department of Haematology, Saiseikai Fukuoka General Hospital, Japan
- Department of Hematology, National Hospital Organization Kyushu Cancer Center, Japan
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Yui Hongo
- Department of Diabetes and Endocrinology, Saiseikai Fukuoka General Hospital, Japan
| | | | - Seiya Kato
- Division of Pathology, Saiseikai Fukuoka General Hospital, Japan
| | - Hironori Kusano
- Department of Pathology, Kurume University School of Medicine, Japan
| | - Shusuke Morizono
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Japan
- Department of Hepatology, Saiseikai Fukuoka General Hospital, Japan
| | - Nobuhiko Higashi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Japan
- Department of Hepatology, Saiseikai Fukuoka General Hospital, Japan
| |
Collapse
|
|
13
|
Lin D, Reddy V, Osman H, Lopez A, Koksal AR, Rhadhi SM, Dash S, Aydin Y. Additional Inhibition of Wnt/β-Catenin Signaling by Metformin in DAA Treatments as a Novel Therapeutic Strategy for HCV-Infected Patients. Cells 2021; 10:790. [PMID: 33918222 PMCID: PMC8065725 DOI: 10.3390/cells10040790] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/24/2021] [Accepted: 03/27/2021] [Indexed: 12/17/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). Although HCV clearance has been improved by the advent of direct-acting antiviral agents (DAA), retrospective studies have shown that the risk of subsequent HCC, while considerably decreased compared with active HCV infection, persists after DAA regimens. However, either the mechanisms of how chronic HCV infection causes HCC or the factors responsible for HCC development after viral eradication in patients with DAA treatments remain elusive. We reported an in vitro model of chronic HCV infection and determined Wnt/β-catenin signaling activation due to the inhibition of GSK-3β activity via serine 9 phosphorylation (p-ser9-GSK-3β) leading to stable non-phosphorylated β-catenin. Immunohistochemical staining demonstrated the upregulation of both β-catenin and p-Ser9-GSK-3β in HCV-induced HCC tissues. Chronic HCV infection increased proliferation and colony-forming ability, but knockdown of β-catenin decreased proliferation and increased apoptosis. Unexpectedly, Wnt/β-catenin signaling remained activated in chronic HCV-infected cells after HCV eradication by DAA, but metformin reversed it through PKA/GSK-3β-mediated β-catenin degradation, inhibited colony-forming ability and proliferation, and increased apoptosis, suggesting that DAA therapy in combination with metformin may be a novel therapy to treat HCV-associated HCC where metformin suppresses Wnt/β-catenin signaling for HCV-infected patients.
Collapse
Affiliation(s)
- Dong Lin
- Laboratory Medicine and Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA; (V.R.); (H.O.); (A.L.); (A.R.K.); (S.M.R.); (S.D.)
| | | | | | | | | | | | | | - Yucel Aydin
- Laboratory Medicine and Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA; (V.R.); (H.O.); (A.L.); (A.R.K.); (S.M.R.); (S.D.)
| |
Collapse
|
|
14
|
An T, Dean M, Flower R, Tatzenko T, Chan HT, Kiely P, Faddy HM. Understanding occult hepatitis C infection. Transfusion 2020; 60:2144-2152. [PMID: 33460181 DOI: 10.1111/trf.16006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 06/16/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Occult hepatitis C infection (OCI) is a type of hepatitis C virus (HCV) infection, defined as the presence of HCV RNA in hepatocytes or peripheral blood mononuclear cells (PBMCs) and the absence of HCV RNA in serum. STUDY DESIGN AND METHODS A literature review was conducted to identify articles that characterized OCI as a disease, including its epidemiology, mode of transmission, pattern of infection, progression, and treatment. RESULTS OCI patients experience a milder degree of inflammatory and cirrhotic changes than patients with chronic hepatitis C. OCI is transmissible parenterally both in vivo and in vitro, however the duration and outcome of OCI remains unclear. OCI is most consistently found in patients with previous hepatitis C disease and hemodialysis patients. Beyond the at-risk populations, OCI has also been demonstrated among healthy individuals and blood donors. CONCLUSIONS This review summarises our current understanding of OCI and suggests areas for further research to improve our understanding of this phenomenon, including a better understanding of its epidemiology and full clinical course. The current understanding of OCI and its clinical implications remain limited. Further standardized detection methods, ongoing surveillance, and investigation of its potential transmissions are required.
Collapse
Affiliation(s)
- Timothy An
- Research and Development, Australia Red Cross Lifeblood, Kelvin Grove, Queensland, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Melinda Dean
- Research and Development, Australia Red Cross Lifeblood, Kelvin Grove, Queensland, Australia.,School of Health and Sports Science, University of the Sunshine Coast, Brisbane, Queensland, Australia
| | - Robert Flower
- Research and Development, Australia Red Cross Lifeblood, Kelvin Grove, Queensland, Australia
| | - Tayla Tatzenko
- Research and Development, Australia Red Cross Lifeblood, Kelvin Grove, Queensland, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Hiu Tat Chan
- Australia Red Cross Lifeblood, Melbourne, Victoria, Australia
| | - Philip Kiely
- Australia Red Cross Lifeblood, Melbourne, Victoria, Australia
| | - Helen M Faddy
- Research and Development, Australia Red Cross Lifeblood, Kelvin Grove, Queensland, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,School of Health and Sports Science, University of the Sunshine Coast, Brisbane, Queensland, Australia
| |
Collapse
|
|
15
|
Mahmoudvand S, Shokri S, Azaran A, Seyedian SS, Makvandi M, Mirzaei H, Sheikhrobat SB. Seronegative occult hepatitis C infection among hemodialysis patients: A prevalence study. Ther Apher Dial 2020; 25:218-224. [PMID: 32510846 DOI: 10.1111/1744-9987.13535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 05/24/2020] [Accepted: 06/04/2020] [Indexed: 11/29/2022]
Abstract
The aim of this study was to investigate the prevalence of occult hepatitis C virus (HCV) infection (OCI) among HD patients. Blood samples were taken from 79 HD patients and their sera were evaluated for the presence of anti-HCV. Both the sera and peripheral blood mononuclear cells (PBMCs) were then checked for HCV RNA by nested reverse transcriptase-polymerase chain reaction. Anti-HCV was positive among 4/79 (5.1%) of the patients. From 75 patients who were negative for anti-HCV, 71 (94.7%) patients were also negative for HCV RNA in sera samples but five of them were positive for HCV RNA in PBMCs. Totally, out of 79 patients, HCV RNA was detected in PBMCs of five (6.3%) patients, indicating that these patients had OCI. No significant difference was observed between the frequency of OCI and gender (P-value = .6). HCV genotype in all five cases of OCI was genotype 3a. Our study showed prevalence rate of 6.3% OCI infection in HD patients. Regarding the serious complications and the clinical importance of OCI in HD patients, sensitive diagnostic methods for identifying HCV RNA in the PBMCs should be implemented for all HD patients.
Collapse
Affiliation(s)
- Shahab Mahmoudvand
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Somayeh Shokri
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Azarakhsh Azaran
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed S Seyedian
- Alimentary Tract Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Manoochehr Makvandi
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Habibollah Mirzaei
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Sheida B Sheikhrobat
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| |
Collapse
|
|
16
|
Min CK, Shakya AK, Lee BJ, Streblow DN, Caposio P, Yurochko AD. The Differentiation of Human Cytomegalovirus Infected-Monocytes Is Required for Viral Replication. Front Cell Infect Microbiol 2020; 10:368. [PMID: 32850474 PMCID: PMC7411144 DOI: 10.3389/fcimb.2020.00368] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 06/15/2020] [Indexed: 12/24/2022] Open
Abstract
Viral dissemination is a key mechanism responsible for persistence and disease following human cytomegalovirus (HCMV) infection. Monocytes play a pivotal role in viral dissemination to organ tissue during primary infection and following reactivation from latency. For example, during primary infection, infected monocytes migrate into tissues and differentiate into macrophages, which then become a source of viral replication. In addition, because differentiated macrophages can survive for months to years, they provide a potential persistent infection source in various organ systems. We broadly note that there are three phases to infection and differentiation of HCMV-infected monocytes: (1) Virus enters and traffics to the nucleus through a virus receptor ligand engagement event that activates a unique signalsome that initiates the monocyte-to-macrophage differentiation process. (2) Following initial infection, HCMV undergoes a "quiescence-like state" in monocytes lasting for several weeks and promotes monocyte differentiation into macrophages. While, the initial event is triggered by the receptor-ligand engagement, the long-term cellular activation is maintained by chronic viral-mediated signaling events. (3) Once HCMV infected monocytes differentiate into macrophages, the expression of immediate early viral (IE) genes is detectable, followed by viral replication and long term infectious viral particles release. Herein, we review the detailed mechanisms of each phase during infection and differentiation into macrophages and discuss the biological significance of the differentiation of monocytes in the pathogenesis of HCMV.
Collapse
Affiliation(s)
- Chan-Ki Min
- Department of Microbiology and Immunology, Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, United States
| | - Akhalesh K Shakya
- Department of Microbiology and Immunology, Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, United States
| | - Byeong-Jae Lee
- Department of Microbiology and Immunology, Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, United States
| | - Daniel N Streblow
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, United States
| | - Patrizia Caposio
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, United States
| | - Andrew D Yurochko
- Department of Microbiology and Immunology, Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, United States
- Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, United States
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, United States
- Center of Excellence in Arthritis and Rheumatology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, United States
| |
Collapse
|
|
17
|
Domínguez-Domínguez L, Lagarde M, Bisbal O, Matarranz M, Rubio R, Pulido F. Sustained virological response at week 12 after interferon-free therapy as criterion for HCV cure definition: Validation in a real-life cohort of HIV-coinfected patients. Enferm Infecc Microbiol Clin 2019; 38:275-278. [PMID: 31668860 DOI: 10.1016/j.eimc.2019.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 07/07/2019] [Accepted: 07/25/2019] [Indexed: 10/25/2022]
Abstract
INTRODUCTION Sustained virological response (SVR) 12 weeks after the end-of-therapy (EOT) has been correlated with SVR24 for HCV-monoinfection. We aim to validate SVR12 as criterion for definition of HCV cure in HIV-coinfected patients treated with all-oral direct-acting antivirals (DAA). METHODS Prospectively observational study including HIV/HCV-coinfected subjects who received DAA and had HCV-RNA measures at weeks 12 and 24 after EOT. Every patient who took ≥1 drug dose was analyzed. RESULTS DAA were prescribed to 423 patients, of whom 387 had HCV-RNA measures both at weeks 12 and 24 after EOT. SVR12 was confirmed in 379/387 patients, while SVR24 was confirmed in 377/387 subjects. The positive-predictive-value (PPV) of SVR12 for SVR24 was 99.5% (95%CI: 98.1-99.9). One of the recurrences was clinically suspected to be a late relapse. CONCLUSIONS SVR12 has a high PPV for HCV cure in HIV/HCV-coinfection, though further follow-up could be necessary for those with deeper immunosuppression.
Collapse
Affiliation(s)
- Lourdes Domínguez-Domínguez
- HIV Unit, Internal Medicine Department, Biomedical Research Institute Imas12, Hospital Universitario 12 de Octubre, Madrid, Spain.
| | - María Lagarde
- HIV Unit, Internal Medicine Department, Biomedical Research Institute Imas12, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Otilia Bisbal
- HIV Unit, Internal Medicine Department, Biomedical Research Institute Imas12, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Mariano Matarranz
- HIV Unit, Internal Medicine Department, Biomedical Research Institute Imas12, Hospital Universitario 12 de Octubre, Madrid, Spain; Servicio de Medicina Interna, Hospital Infanta Leonor, Madrid, Spain
| | - Rafael Rubio
- HIV Unit, Internal Medicine Department, Biomedical Research Institute Imas12, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Federico Pulido
- HIV Unit, Internal Medicine Department, Biomedical Research Institute Imas12, Hospital Universitario 12 de Octubre, Madrid, Spain
| |
Collapse
|
|
18
|
Frías M, Rivero-Juárez A, Téllez F, Palacios R, Jiménez-Arranz Á, Pineda JA, Merino D, Gómez-Vidal MA, Pérez-Camacho I, Camacho Á, Rivero A. Evaluation of hepatitis C viral RNA persistence in HIV-infected patients with long-term sustained virological response by droplet digital PCR. Sci Rep 2019; 9:12507. [PMID: 31467339 PMCID: PMC6715682 DOI: 10.1038/s41598-019-48966-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 08/13/2019] [Indexed: 12/12/2022] Open
Abstract
Several studies have reported the persistence of HCV RNA in liver and/or peripheral blood mononuclear cells (PBMCs) in spite of undetectable viremia in patients who have achieved sustained virological response (SVR). This event, defined as occult HCV infection, remains controversial and low titers of persistent virus may be underestimated because it has not yet been analyzed by a highly sensitive test such as droplet digital PCR (ddPCR). This method provides an alternate ultra-sensitive detection technique for very low numbers of copies of viral RNA or DNA. The aim of this study was to evaluate the persistence of HCV in HIV-coinfected patients with long-term SVR using ddPCR. For each patient, the presence of HCV RNA in serum and PBMCs at baseline was determined by nested RT-ddPCR. Patients with HCV RNA in PBMCs at baseline were followed until the end of the study. One hundred and twenty-three patients were analyzed for persistence of HCV RNA in serum and PBMCs. Persistence of HCV was not found in serum in any patient. HCV RNA was detected in PBMCs in one patient (0.81%; 95% CI: 0.04–3.94) and resolved spontaneously during follow-up. Persistence of HCV RNA in PBMCs is not a common event in HIV/HCV co-infected patients with long-term SVR evaluated by RT-ddPCR.
Collapse
Affiliation(s)
- Mario Frías
- Unidad de Enfermedades Infecciosas. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba, Córdoba, Spain
| | - Antonio Rivero-Juárez
- Unidad de Enfermedades Infecciosas. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba, Córdoba, Spain.
| | - Francisco Téllez
- Unidad Gestión Clínica Enfermedades Infecciosas, Hospital La Línea, AGS Campo de Gibraltar, Cádiz, Spain
| | - Rosario Palacios
- Unidad de Enfermedades Infecciosas. Hospital Universitario Virgen de la Victoria, Complejo Hospitalario Provincial de Málaga, Málaga, Spain
| | - Álvaro Jiménez-Arranz
- Unidad de Genómica. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain
| | - Juan A Pineda
- Unidad de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Instituto de Biomedicina de Sevilla (iBiS), Sevilla, Spain
| | - Dolores Merino
- Unidad de Enfermedades Infecciosas, Hospitales Juan Ramón Jiménez e Infanta Elena de Huelva, Huelva, Spain
| | | | - Inés Pérez-Camacho
- Unidad de Enfermedades Infecciosas, Hospital de Poniente, El Ejido, Spain
| | - Ángela Camacho
- Unidad de Enfermedades Infecciosas. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba, Córdoba, Spain
| | - Antonio Rivero
- Unidad de Enfermedades Infecciosas. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba, Córdoba, Spain
| |
Collapse
|
|
19
|
Cotter TG, Jensen DM. Glecaprevir/pibrentasvir for the treatment of chronic hepatitis C: design, development, and place in therapy. Drug Des Devel Ther 2019; 13:2565-2577. [PMID: 31534310 PMCID: PMC6681154 DOI: 10.2147/dddt.s172512] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 06/27/2019] [Indexed: 12/13/2022] Open
Abstract
Direct-acting antiviral (DAA) therapy has changed the landscape of hepatitis C virus (HCV) management and has changed the focus to the possibility of HCV elimination in the near future. Glecaprevir, an NS3/4A protease inhibitor, and pibrentasvir, an HCV NS5A inhibitor, have addressed many of the existing shortcomings in the DAA therapy spectrum. This combination has proven to be a highly efficacious pan-genotypic DAA with a high barrier to resistance as a once-daily, all-oral medication. This review explores the design and development of glecaprevir and pibrentasvir, its place in current HCV management in the midst of a myriad of DAA therapy options, and also remaining challenges.
Collapse
Affiliation(s)
- Thomas G Cotter
- Center for Liver Diseases, The University of Chicago Medicine, Chicago, IL, USA
| | - Donald M Jensen
- Section of Hepatology, RUSH University Medical Center, Chicago, IL, USA
| |
Collapse
|
|
20
|
Wang Y, Rao H, Chi X, Li B, Liu H, Wu L, Zhang H, Liu S, Zhou G, Li N, Niu J, Wei L, Zhao J. Detection of residual HCV-RNA in patients who have achieved sustained virological response is associated with persistent histological abnormality. EBioMedicine 2019; 46:227-235. [PMID: 31345785 PMCID: PMC6711338 DOI: 10.1016/j.ebiom.2019.07.043] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 07/15/2019] [Accepted: 07/16/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Whether achieving sustained virological response (SVR) in patients with hepatitis C attains complete elimination of hepatitis C virus (HCV) is unknown, because occult HCV infection (OCI), defined as the detection of HCV-RNA in hepatocytes or peripheral blood mononuclear cells (PBMC) in absence of serum HCV-RNA, may occur. We thus investigated the prevalence and clinical relevance of OCI. METHODS Subjects from three hospitals who had achieved serum HCV clearance, including 60 of Direct-acting antiviral agents (DAAs) induced SVR, 50 of pegylated interferon plus ribavirin (PR) induced SVR, and 30 of spontaneous resolution, were subjected to detect HCV-RNA in liver by robust RNAscope assay and PBMC by qPCR. Paired liver biopsies at baseline and at SVR24 were analyzed. RESULTS OCI was detected in 16 of 140 subjects (11.4%), with 15.0% in DAA-based group, 10.0% in PR group and 6.7% in spontaneously resolved group. In DAA-based subgroups, the incidence of OCI was gradually increased in group of solely DAA(s) therapy, combining DAA and PR therapy and combining DAA and ribavirin therapy. OCI is more frequent in patients with genotype 3. No correlation between baseline viral load, interleukin-28B genotype, baseline transaminases, post-SVR transaminases and OCI were found. However, OCI was significantly linked with severity of fibrosis and active inflammation at post-SVR, even considering basal fibrosis status. In addition, both the magnitude and the frequency of fibrosis regression were lower in patients with OCI than in those without OCI. In the multivariate analysis, PR therapy was identified an independent negative prognostic factor for both hepatic inflammation (P = .022) and fibrosis regression (P = .015). Importantly, we found HCV relapse in one of the OCI patients at 48 weeks after the end of PR treatment. CONCLUSIONS HCV-RNA can persist in hepatocytes and/or PBMC in a certain of patients who achieved spontaneous or treatment-induced HCV RNA clearance from serum and associated with persistent histological abnormality. Our findings provide new insights into cure of HCV and could influence the following-up scenario after SVR.
Collapse
Affiliation(s)
- Yijin Wang
- Department of Pathology and Hepatology, the 5th Medical Center, Chinese PLA General Hospital, China
| | - Huiying Rao
- Peking University Hepatology Institute, Peking University People's Hospital, Peking University Health Science Center, Beijing, China
| | - Xiumei Chi
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
| | - Boan Li
- Center for Clinical Laboratory, the 5th Medical Center, Chinese PLA General Hospital, China
| | - Hongyang Liu
- Department of Pathology and Hepatology, the 5th Medical Center, Chinese PLA General Hospital, China
| | - Liyuan Wu
- Department of Pathology and Hepatology, the 5th Medical Center, Chinese PLA General Hospital, China
| | - Hao Zhang
- Center for Clinical Laboratory, the 5th Medical Center, Chinese PLA General Hospital, China
| | - Shuhong Liu
- Department of Pathology and Hepatology, the 5th Medical Center, Chinese PLA General Hospital, China
| | - Gaungde Zhou
- Department of Pathology and Hepatology, the 5th Medical Center, Chinese PLA General Hospital, China
| | - Na Li
- Advanced Cell Diagnostics, 3960 Point Eden Way, Hayward, CA 94545, USA
| | - Junqi Niu
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China.
| | - Lai Wei
- Beijing Tsinghua Changgung Hospital, Tsinghua University, China.
| | - Jingmin Zhao
- Department of Pathology and Hepatology, the 5th Medical Center, Chinese PLA General Hospital, China.
| |
Collapse
|
|
21
|
Pisaturo M, Minichini C, Starace M, Caroprese M, Macera M, Brancaccio G, De Pascalis S, Santonicola A, Galeota Lanza A, Zampino R, Cotticelli G, Sagnelli E, Gaeta GB, Coppola N. Hepatitis C late relapse in patients with directly acting antiviral-related sustained virological response at week 12. Liver Int 2019; 39:844-853. [PMID: 30554459 DOI: 10.1111/liv.14025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 11/21/2018] [Accepted: 12/02/2018] [Indexed: 12/15/2022]
Abstract
AIM The aim of the present study was to identify, among the patients with failure to DAA regimen, those with a late relapse (after the achievement of a sustained virological response at week 12) and to characterize the clinical, epidemiological and virological features of these patients. MATERIAL AND METHODS A total of 129 HCV patients with non-response to an IFN-free regimen were enrolled. Sanger sequencing of NS3, NS5A and NS5B was performed at failure by home-made protocols. RESULTS Of the 129 patients enrolled, 8 (6.2%) experienced a breakthrough, 15 (11.7%) non-response, 99 (76.7%) a relapse by week 12 after the end of DAA therapy, and 7 (5.4%) a late relapse (after week 12; median 24 weeks, range 24-72). For two of the seven patients with a late relapse, a serum sample collected before the start of the DAA regimen was available; phylogenetic analysis showed no change in sequences of NS3, NS5A and NS5B regions, suggesting a reactivation of the initial HCV strain; for the remaining five patients, no serum collected before the DAA regimen was available, and thus, a re-infection cannot be excluded. CONCLUSIONS Although a late relapse is infrequent, the study suggests a post-treatment follow-up of 72 weeks.
Collapse
Affiliation(s)
- Mariantonietta Pisaturo
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania, Naples, Italy
| | - Carmine Minichini
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania, Naples, Italy
| | - Mario Starace
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania, Naples, Italy
| | - Mara Caroprese
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania, Naples, Italy
| | - Margherita Macera
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania, Naples, Italy
| | - Giuseppina Brancaccio
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania, Naples, Italy
| | - Stefania De Pascalis
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania, Naples, Italy
| | | | | | - Rosa Zampino
- Department of Medical, Surgical, Neurological, Metabolic, and Geriatric Sciences, University of Campania "L. Vanvitelli", Naples, Italy
| | - Gaetano Cotticelli
- Internal Medicine and Hepatology, Department of Clinical and Experimental Medicine, University of Campania "L. Vanvitelli", Naples, Italy
| | - Evangelista Sagnelli
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania, Naples, Italy
| | - Giovanni Battista Gaeta
- Infectious Diseases and Viral Hepatitis, Department of Mental and Physical Health and Preventive Medicine, University of Campania, Naples, Italy
| | - Nicola Coppola
- Laboratory for the Identification of Prognostic Factors of Response to the Treatment Against Infectious Diseases, University of Campania, Naples, Italy.,Infectious Diseases Unit, AO Caserta, Caserta, Italy
| |
Collapse
|
|
22
|
Del Bello A, Abravanel F, Alric L, Lavayssiere L, Lhomme S, Bellière J, Izopet J, Kamar N. No evidence of occult hepatitis C or E virus infections in liver-transplant patients with sustained virological response after therapy with direct acting agents. Transpl Infect Dis 2019; 21:e13093. [PMID: 30972874 DOI: 10.1111/tid.13093] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 02/21/2019] [Accepted: 04/07/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS It has been recently suggested that occult hepatitis C virus (HCV) infection and hepatitis E virus (HEV) reactivation might occur after direct acting antiviral agent-induced (DAA-induced) sustained virological response (SVR). The aim of our study was to identify occult HCV and HEV infection in a cohort of organ transplant patients who had achieved SVR and had persistent elevation in liver-enzyme levels. PATIENTS AND METHOD Sixty-six liver and/or kidney transplant patients were treated with DAAs. All but one achieved SVR12. Twenty-nine (8-39) months post-SVR12, 8 of the 65 patients (12.3%) who achieved SVR12 had persistently elevated liver enzyme levels. In 1 patient, this was related to hepatitis B virus reactivation. In the 7 remaining patients, blood samples (n = 7), liver biopsies (n = 4), and peripheral blood mononuclear cells (PBMCs) (n = 7) were collected simultaneously in order to identify occult HCV or HEV infection. RESULTS Hepatitis C virus RNA and HEV RNA were not detected in serum, liver tissues, or PBMCs. No HEV reactivation was observed after HCV clearance in patients who had anti-HEV IgG. CONCLUSION Our study suggests that there is no occult HCV or HEV infection in transplant patients after successful treatment of HCV infection with DAAs, even in patients with a persistent elevation of liver enzyme levels. However, due to the small number of patients included in our study, this finding should be confirmed in a larger cohort.
Collapse
Affiliation(s)
- Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,Université Paul Sabatier, Toulouse, France
| | - Florence Abravanel
- Department of Virology, Institut Fédératif de Biologie de Purpan, CHU Toulouse, France.,Centre de Physiopathologie de Toulouse Purpan, CHU Toulouse, France.,INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France
| | - Laurent Alric
- Department of Internal Medicine and Digestive Diseases, CHU Purpan, UMR 152 Pharma Dev, IRD Toulouse 3 University, Toulouse, France
| | - Laurence Lavayssiere
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Sébastien Lhomme
- Department of Virology, Institut Fédératif de Biologie de Purpan, CHU Toulouse, France.,Centre de Physiopathologie de Toulouse Purpan, CHU Toulouse, France.,INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France
| | - Julie Bellière
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,Université Paul Sabatier, Toulouse, France
| | - Jacques Izopet
- Department of Virology, Institut Fédératif de Biologie de Purpan, CHU Toulouse, France.,Centre de Physiopathologie de Toulouse Purpan, CHU Toulouse, France.,INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,Université Paul Sabatier, Toulouse, France.,INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France
| |
Collapse
|
|
23
|
Yuan G, Rong L, Liu J, Zhang Z, Hu C, Chen M, Ma L, Zhang YY, Li YP, Zhou Y. Serum‑derived hepatitis C virus can infect human glioblastoma cell line SF268 and activate the PI3K‑Akt pathway. Mol Med Rep 2019; 19:4441-4448. [PMID: 30896873 DOI: 10.3892/mmr.2019.10063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 02/08/2019] [Indexed: 11/06/2022] Open
Abstract
Extra‑hepatic manifestations are frequently observed in hepatitis C virus (HCV)‑infected patients; however the underlying mechanisms remain largely unknown. In the present study, the human glioblastoma SF268 cell line (the precise origin of the cell type is not clear) was infected with HCV using HCV‑positive serum, and viral replication was assessed by immunofluorescence, reverse transcription‑polymerase chain reaction (PCR), quantitative PCR and western blotting following infection. HCV core protein and HCV RNA were detected in HCV‑positive serum‑infected SF268 cells at day 4 post‑infection, while no infection was observed in cells exposed to HCV‑negative serum. The mean HCV RNA levels at day 4 post‑infection were up to 5.00 IU/ml log10; however, HCV RNA and immunostaining for core protein were negative when cultured to day 6 or longer. The data suggest that human glioblastoma SF268 cells were transiently infected with HCV. AKT serine/threonine kinase phosphorylation was also detected in HCV‑infected SF268 cells at day 4 post‑infection. To the best of our knowledge, this is the first demonstration that a human glioblastoma cell line can be infected with serum‑derived HCV. The results provide evidence that HCV infection can occur in cells of the central nervous system. Neurological disorder‑associated phosphoinositide 3‑kinase‑AKT signaling pathway was activated in parallel with HCV infection, suggesting that SF268 may serve as an in vitro model for investigating HCV‑nervous system cell interactions.
Collapse
Affiliation(s)
- Guosheng Yuan
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Liang Rong
- Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Junwei Liu
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Zhenzhen Zhang
- Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Chengguang Hu
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Mingxiao Chen
- Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Ling Ma
- Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | | | - Yi-Ping Li
- Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Yuanping Zhou
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| |
Collapse
|
|
24
|
Mekky MA, Sayed HI, Abdelmalek MO, Saleh MA, Osman OA, Osman HA, Morsy KH, Hetta HF. Prevalence and predictors of occult hepatitis C virus infection among Egyptian patients who achieved sustained virologic response to sofosbuvir/daclatasvir therapy: a multi-center study. Infect Drug Resist 2019; 12:273-279. [PMID: 30774394 PMCID: PMC6348965 DOI: 10.2147/idr.s181638] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background Occult hepatitis C virus (HCV) infection (OCI) is characterized by the detection of HCV-RNA in non-serum reservoirs, such as peripheral blood mononuclear cells (PBMCs) and/or hepatocytes with undetectable HCV-RNA or antibodies in the serum. In this study, we tried to evaluate the prevalence and possible predictors of OCI in patients who achieved sustained virologic response (SVR) post sofosbuvir/daclatasvir (SOF/DCV) therapy. Patients and methods A cross-sectional multicenter study was designed to enroll 1,280 HCV-infected patients who received SOF (400 mg) plus DCV (60 mg) once daily ± ribavirin regimen for 12 weeks and achieved SVR 12 weeks post treatment. They were randomly recruited from three dedicated Egyptian centers for management of HCV. Real-time PCR was performed to detect HCV-RNA in serum and PBMCs and to evaluate the different risk factors pertaining to the existence of OCI. Results HCV-RNA was detected in PBMCs of 50 (3.9%) of them. All OCI cases exhibited significant fibrosis score and raised pre-treatment alanine aminotransferase (ALT) levels. Logistic regression analysis comparing OCI with non-OCI revealed that high pre-treatment viral load, raised ALT, advanced fibrosis score, prolonged prothrombin time, low albumin, Child B score, antiviral experienced patients, and raised bilirubin are the most significant predictor for the possibility of OCI presence with Odds Ratio as 7.03, 5.13, 4.4, 2.68, 2.52, 1.9, 1.5, and 1.2, respectively. Conclusion In spite of its remote possibility, OCI post SOF/DCV therapy may be present in some cases, and this may entail a re-auditing for the definition of SVR by dual testing in both serum and PBMCs.
Collapse
Affiliation(s)
- Mohamed A Mekky
- Department of Tropical Medicine and Gastroenterology, Assiut University Hospital, Assiut, Egypt
| | - Hani I Sayed
- Center for Management of Viral Hepatitis, Ministry of Health, Assiut, Egypt
| | - Mohamed O Abdelmalek
- Department of Tropical Medicine and Gastroenterology, Assiut University Hospital, Assiut, Egypt
| | - Medhat A Saleh
- Department of Public Health and Community Medicine, Assiut University, Assiut, Egypt
| | - Osman A Osman
- Department of Tropical Medicine and Gastroenterology, Assiut University Hospital, Assiut, Egypt
| | - Heba A Osman
- Department of Tropical Medicine and Gastroenterology, South Valley University Hospital, Qena, Egypt
| | - Khairy H Morsy
- Department of Tropical Medicine and Gastroenterology, Sohag University Hospital, Sohag, Egypt
| | - Helal F Hetta
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt, .,Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA,
| |
Collapse
|
|
25
|
Hayashi K, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Hirooka Y, Toyoda H, Kumada T, Hattori M, Katano Y, Goto H. Late relapse of hepatitis C virus in patients with sustained virological response after daclatasvir and asunaprevir therapy. J Viral Hepat 2018; 25:1446-1451. [PMID: 29993164 DOI: 10.1111/jvh.12967] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 06/21/2018] [Accepted: 06/27/2018] [Indexed: 12/12/2022]
Abstract
The optimal term of follow-up for patients who achieve sustained virological responses (SVR) is an important topic because of the widespread use of direct-acting antivirals (DAA), which achieve a high SVR rate. Investigations of long-term follow-up among patients with SVR after interferon (IFN) therapy have reported that approximately 80%-100% of patients maintained SVR. However, the long-term durability of SVR to DAA treatment is unknown. The aim of this study was to evaluate the incidence of late relapse in patients who achieved SVR with daclatasvir (DCV) and asunaprevir (ASV). Four hundred and thirteen patients infected with hepatitis C virus (HCV) genotype 1b who completed ASV and DCV treatment and achieved SVR were selected. Patients who were persistently negative for serum HCV RNA at 24 weeks after withdrawal of DCV and ASV were considered to have SVR24. Mean follow-up period was 21.5 months (range, 4.8-30.3 months) after SVR24. Four patients redeveloped HCV RNA in serum at 6, 12, 12 and 26 months, respectively, after achieving SVR24. Results of molecular analysis by phylogenetic tree of HCV nonstructural protein 3 and 5A regions from late relapse indicated that the same strain was present at pretreatment and late relapse. In conclusion, late relapse by the original HCV strain was confirmed by direct sequencing in 4 of 413 patients with SVR to ASV and DCV. Although a few patients may develop late relapse, SVR achieved with all oral DAA therapy is as durable as that with IFN therapy.
Collapse
Affiliation(s)
- Kazuhiko Hayashi
- Department of Gastroenterology and Hepatology, Meijo Hospital, Nagoya, Japan.,Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Takashi Kumada
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Masashi Hattori
- Department of Gastroenterology, Yamashita Hospital, Ichinomiya, Japan
| | - Yoshiaki Katano
- Department of Internal Medicine, Banbuntane Hotokukai Hospital, School of Medicine, Fujita Health University, Nagoya, Japan
| | - Hidemi Goto
- Department of Gastroenterology and Hepatology, Meijo Hospital, Nagoya, Japan.,Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| |
Collapse
|
|
26
|
Mercuri L, Thomson EC, Hughes J, Karayiannis P. Quasispecies Changes with Distinctive Point Mutations in the Hepatitis C Virus Internal Ribosome Entry Site (IRES) Derived from PBMCs and Plasma. Adv Virol 2018; 2018:4835252. [PMID: 30581467 PMCID: PMC6276526 DOI: 10.1155/2018/4835252] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 11/11/2018] [Indexed: 12/12/2022] Open
Abstract
The 5' untranslated region (UTR) of the hepatitis C virus (HCV) genome contains the internal ribosome entry site (IRES), a highly conserved RNA structure essential for cap-independent translation of the viral polyprotein. HCV, apart from the liver, is thought to be associated with lymphocyte subpopulations of peripheral blood mononuclear cells (PBMCs), in lymph nodes and brain tissue. In this study, RT-PCR, cloning, and sequence analysis were employed to investigate the quasispecies nature of the 5'UTR following extraction of viral RNA from PBMCs and plasma of HCV infected individuals. The nucleotide variation between IRES-derived sequences from PBMCs and plasma indicated the existence of polymorphic sites within the IRES. HCV isolates had divergent variants with unique mutations particularly at positions 107, 204, and 243 of the IRES. Most of the PBMC-derived sequences contained an A-A-A variant at these positions. The mutations associated with the IRESes suggested the presence of unique quasispecies populations in PBMCs compared with plasma.
Collapse
Affiliation(s)
- Luca Mercuri
- Hepatology Section, Division of Medicine, Faculty of Medicine, Imperial College, London, UK
| | - Emma C. Thomson
- University of Glasgow MRC Centre for Virus Research, Glasgow, UK
| | - Joseph Hughes
- University of Glasgow MRC Centre for Virus Research, Glasgow, UK
| | | |
Collapse
|
|
27
|
Iwona BO, Karol P, Kamila CC, Pollak A, Hanna B, Agnieszka P, Andrzej H, Kosińska J, Płoski R, Tomasz L, Marek R. Next-generation sequencing analysis of new genotypes appearing during antiviral treatment of chronic hepatitis C reveals that these are selected from pre-existing minor strains. J Gen Virol 2018; 99:1633-1642. [PMID: 30394872 DOI: 10.1099/jgv.0.001160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Coinfection with more than one hepatitis C virus (HCV) genotype is common, but its dynamics, particularly during antiviral treatment, remain largely unknown. We employed next-generation sequencing (NGS) to analyse sequential serum and peripheral blood mononuclear cell (PBMC) samples in seven patients with transient presence or permanent genotype change during antiviral treatment with interferon and ribavirin. Specimens were collected right before the therapy initiation and at 2, 4, 6, 8, 12, 20, 24, 36, 44 and 48 weeks during treatment and 6 months after treatment ceased. A mixture of two different genotypes was detected in the pretreatment samples from five patients and the minor genotype constituted 0.02 to 38 %. A transient or permanent change of the predominant genotype was observed in six patients. In three cases genotype 3 was replaced as the predominant genotype by genotype 4, in two cases genotype 3 was replaced by genotype 1, and in one subject genotype 1 was replaced by genotype 4. The PBMC- and serum-derived sequences were frequently discordant with respect to genotype and/or genotype proportions. In conclusion, pre-existing minor HCV genotypes can be selected rapidly during antiviral treatment and become transiently or permanently predominant. In coinfections involving genotype 3, genotype 3 was eliminated first from both the serum and PBMC compartments. The PBMC- and serum-derived HCV sequences were frequently discordant with respect to genotype and/or genotype proportions, suggesting that they constitute separate compartments with their own dynamics.
Collapse
Affiliation(s)
- Bukowska-Ośko Iwona
- 1Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
| | - Perlejewski Karol
- 1Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
| | - Caraballo Cortés Kamila
- 1Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
| | - Agnieszka Pollak
- 2Institute of Physiology and Pathology of Hearing, 17 Mokra Street, Kajetany 05-830 Nadarzyn, Poland
| | - Berak Hanna
- 3Hospital for Infectious Diseases, 37 Wolska Street, 01-201 Warsaw, Poland
| | - Pawełczyk Agnieszka
- 1Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
| | - Horban Andrzej
- 3Hospital for Infectious Diseases, 37 Wolska Street, 01-201 Warsaw, Poland
- 4Department of Infectious Diseases, Warsaw Medical University, Warsaw, Poland
| | - Joanna Kosińska
- 5Department of Medical Genetics, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
| | - Rafał Płoski
- 5Department of Medical Genetics, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
| | - Laskus Tomasz
- 1Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
| | - Radkowski Marek
- 1Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 3C Pawinskiego Street, 02-106 Warsaw, Poland
| |
Collapse
|
|
28
|
Nikitina E, Larionova I, Choinzonov E, Kzhyshkowska J. Monocytes and Macrophages as Viral Targets and Reservoirs. Int J Mol Sci 2018; 19:E2821. [PMID: 30231586 PMCID: PMC6163364 DOI: 10.3390/ijms19092821] [Citation(s) in RCA: 157] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/10/2018] [Accepted: 09/14/2018] [Indexed: 02/07/2023] Open
Abstract
Viruses manipulate cell biology to utilize monocytes/macrophages as vessels for dissemination, long-term persistence within tissues and virus replication. Viruses enter cells through endocytosis, phagocytosis, macropinocytosis or membrane fusion. These processes play important roles in the mechanisms contributing to the pathogenesis of these agents and in establishing viral genome persistence and latency. Upon viral infection, monocytes respond with an elevated expression of proinflammatory signalling molecules and antiviral responses, as is shown in the case of the influenza, Chikungunya, human herpes and Zika viruses. Human immunodeficiency virus initiates acute inflammation on site during the early stages of infection but there is a shift of M1 to M2 at the later stages of infection. Cytomegalovirus creates a balance between pro- and anti-inflammatory processes by inducing a specific phenotype within the M1/M2 continuum. Despite facilitating inflammation, infected macrophages generally display abolished apoptosis and restricted cytopathic effect, which sustains the virus production. The majority of viruses discussed in this review employ monocytes/macrophages as a repository but certain viruses use these cells for productive replication. This review focuses on viral adaptations to enter monocytes/macrophages, immune escape, reprogramming of infected cells and the response of the host cells.
Collapse
Affiliation(s)
- Ekaterina Nikitina
- Department of Episomal-Persistent DNA in Cancer- and Chronic Diseases, German Cancer Research Center, 69120 Heidelberg, Germany.
- Department of Oncovirology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russia.
- Department of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk 634050, Russia.
| | - Irina Larionova
- Department of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk 634050, Russia.
- Department of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russia.
| | - Evgeniy Choinzonov
- Head and Neck Department, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk 634050, Russia.
| | - Julia Kzhyshkowska
- Department of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk 634050, Russia.
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, 68167 Heidelberg, Germany.
| |
Collapse
|
|
29
|
Bunchorntavakul C, Mitrani R, Reddy KR. Advances in HCV and Cryoglobulinemic Vasculitis in the Era of DAAs: Are We at the End of the Road? J Clin Exp Hepatol 2018; 8:81-94. [PMID: 29743799 PMCID: PMC5938331 DOI: 10.1016/j.jceh.2017.11.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 11/30/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C Virus (HCV)-related Mixed Cryoglobulinemia (MC) is a unique condition with complex pathogenesis that involves HCV antigen-driven B-lymphocyte clonal proliferation and mutagenesis. Clinical spectrum of MC ranges from asymptomatic state to clinically-apparent vasculitis involving multiple organs. In the era of Direct-Acting Antiviral (DAA) therapy, patients with HCV-related MC achieve high rates of viral clearance that is commonly accompanied by an improvement in clinical symptoms as well as immunological profiles. Rituximab, either alone or in combination with DAA, has also been shown to be effective. Nevertheless, there have been limited and somewhat conflicting data, particularly over the long-term, regarding the rate and degree of clinical response of MC following DAA therapy. It appears that we have come quite a long way in the last decade with this condition. As with non-MC related HCV, undoubtedly long term outcome data will be forthcoming over the next few years. As we move forward successful therapy of HCV is not likely to be a challenge in contrast to access to therapy.
Collapse
Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Rajavithi Road, Ratchathewi, Bangkok 10400, Thailand
| | - Robert Mitrani
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - K. Rajender Reddy
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA
| |
Collapse
|
|
30
|
Abdelmoemen G, Khodeir SA, Abou-Saif S, Kobtan A, Abd-Elsalam S. Prevalence of occult hepatitis C virus among hemodialysis patients in Tanta university hospitals: a single-center study. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2018; 25:5459-5464. [PMID: 29214477 DOI: 10.1007/s11356-017-0897-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 12/01/2017] [Indexed: 06/07/2023]
Abstract
Occult hepatitis C virus infection (OCI) is a newly defined type of infection by the chronic hepatitis virus (HCV) distinguished by the existence of HCV RNA in liver tissue and/or peripheral blood mononuclear cells (PBMCs) in patients whose plasma are devoid of both positive serology and RNA. Patients on maintenance hemodialysis evince a higher HCV prevalence than the general population due to high nosocomial transmission by the dialysis units. We investigated the prevalence of occult HCV infection in patients attending our university hemodialysis centers for maintenance hemodialysis. Sixty-two CHD patients negative for serum HCV tests were enrolled in the study. PMNCs were tested by real-time PCR for the presence of HCV RNA. For the 62 patients, the average duration since starting dialysis was 32.7 months and the mean (SD) alanine transaminase and aspartate transaminase were 25.74 ± 9.75 and 28.81 ± 11.32 IU/l, respectively. Out of the 62 CHD patients negative for serum anti-HCV and HCV RNA patients, only three (4.84%) were shown to have HCV RNA in their PBMCs implying the diagnosis of OCI; their viral load range was 1.24-4.15 IU/ml. All three OCI-proven patients gave no history of hepatic disease. In this study, we found that patients considered to be free of HCV can have HCV replicating in their PBMCs. This awareness points to the possibility of HCV being transmitted from apparently uninfected persons. A positive HCV RNA detection in PBMCs is dependable in determining OCI among high-risk subjects particularly when a liver biopsy is not an option. HCV transmission can occur through hemodialysis units signaling incorrect application of infection control measures in our Egyptian dialysis units. Additional studies on hemodialysis patients are necessary to realize the true magnitude of OCI among this patient group and to highlight the importance of incorporating HCV viral assays in PBMCs into the diagnostic algorithm.
Collapse
Affiliation(s)
- Ghada Abdelmoemen
- Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | - Sabry Abou-Saif
- Department of Tropical Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Abdelrahman Kobtan
- Department of Tropical Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Sherief Abd-Elsalam
- Department of Tropical Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt.
- Tropical Medicine Department, Tanta University Hospital, El Geish Street, Tanta, Gharbia Governorate, Egypt.
| |
Collapse
|
|
31
|
Authentic Patient-Derived Hepatitis C Virus Infects and Productively Replicates in Primary CD4 + and CD8 + T Lymphocytes In Vitro. J Virol 2018; 92:JVI.01790-17. [PMID: 29167333 DOI: 10.1128/jvi.01790-17] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 11/09/2017] [Indexed: 12/17/2022] Open
Abstract
Accumulated evidence indicates that immune cells can support the replication of hepatitis C virus (HCV) in infected patients and in culture. However, there is a scarcity of data on the degree to which individual immune cell types support HCV propagation and on characteristics of virus assembly. We investigated the ability of authentic, patient-derived HCV to infect in vitro two closely related but functionally distinct immune cell types, CD4+ and CD8+ T lymphocytes, and assessed the properties of the virus produced by these cells. The HCV replication system in intermittently mitogen-stimulated T cells was adapted to infect primary human CD4+ or CD8+ T lymphocytes. HCV replicated in both cell types although at significantly higher levels in CD4+ than in CD8+ T cells. Thus, the HCV RNA replicative (negative) strand was detected in CD4+ and CD8+ cells at estimated mean levels ± standard errors of the means of 6.7 × 102 ± 3.8 × 102 and 1.2 × 102 ± 0.8 × 102 copies/μg RNA, respectively (P < 0.0001). Intracellular HCV NS5a and/or core proteins were identified in 0.9% of CD4+ and in 1.2% of CD8+ T cells. Double staining for NS5a and T cell type-specific markers confirmed that transcriptionally competent virus replicated in both cell types. Furthermore, an HCV-specific protease inhibitor, telaprevir, inhibited infection in both CD4+ and CD8+ cells. The emergence of unique HCV variants and the release of HCV RNA-reactive particles with biophysical properties different from those of virions in plasma inocula suggested that distinct viral particles were assembled, and therefore, they may contribute to the pool of circulating virus in infected patients.IMPORTANCE Although the liver is the main site of HCV replication, infection of the immune system is an intrinsic characteristic of this virus independent of whether infection is symptomatic or clinically silent. Many fundamental aspects of HCV lymphotropism remain uncertain, including the degree to which different immune cells support infection and contribute to virus diversity. We show that authentic, patient-derived HCV productively replicates in vitro in two closely related but functionally distinct types of T lymphocytes, CD4+ and CD8+ cells. The display of viral proteins and unique variants, the production of virions with biophysical properties distinct from those in plasma serving as inocula, and inhibition of replication by an antiviral agent led us to ascertain that both T cell subtypes supported virus propagation. Infection of CD4+ and CD8+ T cells, which are central to adaptive antiviral immune responses, can directly affect HCV clearance, favor virus persistence, and decisively influence the development and progression of hepatitis C.
Collapse
|
|
32
|
Sajjad EA, Radkowski M, Perkowska-Ptasińska A, Pacholczyk M, Durlik M, Fedorowicz M, Pietrzak R, Ziarkiewicz-Wróblewska B, Włodarski P, Malejczyk J. Negative Correlation Between Hepatitis C Virus (HCV) and Let-7 MicroRNA Family in Transplanted Livers: The Role of rs868 Single-Nucleotide Polymorphism. Ann Transplant 2017; 22:638-645. [PMID: 29061957 PMCID: PMC6248281 DOI: 10.12659/aot.905540] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background Genetic alterations of TGF-β pathway members, including its transmembrane receptor, TGFBR1, may influence the course of HCV infection. Rs868 is a single-nucleotide polymorphism of the 3′UTR region of TGFBR1, located in a binding site for the conserved let-7/miR98 microRNA family. Previously, we demonstrated a favorable course of hepatitis C recurrence after liver transplantation in rs868 AG genotype of the transplanted liver when compared to rs868 AA. The aim of the present study was to confirm the biological effect of rs868. Material/Methods HepG2 cell line was transfected with luciferase vectors cloned with 3′UTR of TGFBR1 gene encompassing different rs868 alleles. Post-transplant liver biopsies from 61 patients with HCV-related end-stage liver disease were evaluated histopathologically and analyzed for the expression of TGFBR1 mRNA, let-7/miR98 microRNAs, HCV RNA load, and rs868 genotype. Results Luciferase expression was significantly lower in the A allele-containing vector. TGFBR1 mRNA and HCV RNA load were correlated negatively with let-7/miR98 microRNAs and this correlation was significantly stronger for rs868 AG compared to AA genotype. A strong positive correlation was demonstrated between TGFBR1 and HCV in both genotypes. In AG heterozygotes, let-7/miR98 microRNAs showed a strong negative correlation with periportal or periseptal interface hepatitis (Ishak A score). Conclusions There is a negative correlation between let-7/miR98 microRNAs and HCV viral load and TGFBR1 mRNA after liver transplantation. In the rs868 AG heterozygotes, this correlation was stronger and there was a negative correlation between let-7/miR98 and Ishak A score, which is in concordance with the previously demonstrated protective role of this genotype in post-transplant hepatitis C recurrence.
Collapse
Affiliation(s)
- Emir Ahmed Sajjad
- Department of Histology and Embryology, Centre for Biostructure Research, Medical University of Warsaw, Warsaw, Poland
| | - Marek Radkowski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Agnieszka Perkowska-Ptasińska
- Department of Transplantology, Nephrology and Internal Medicine, Medical University of Warsaw, Transplantation Institute, Warsaw, Poland
| | - Marek Pacholczyk
- Department of General Surgery and Transplantology, Medical University of Warsaw, Transplantation Institute, Warsaw, Poland
| | - Magdalena Durlik
- Department of Transplantology, Nephrology and Internal Medicine, Medical University of Warsaw, Transplantation Institute, Warsaw, Poland
| | - Mikołaj Fedorowicz
- Department of Histology and Embryology, Centre for Biostructure Research, Medical University of Warsaw, Warsaw, Poland
| | - Renata Pietrzak
- Department of Histology and Embryology, Centre for Biostructure Research, Medical University of Warsaw, Warsaw, Poland
| | | | - Paweł Włodarski
- Department of Histology and Embryology, Centre for Biostructure Research, Medical University of Warsaw, Warsaw, Poland
| | - Jacek Malejczyk
- Department of Histology and Embryology, Centre for Biostructure Research, Medical University of Warsaw, Warsaw, Poland
| |
Collapse
|
|
33
|
Wu YT, Xu Z, Chen HR, Arshad B, Li HY, Wu KN, Kong LQ. A Novel Antiviral Treatment of Hepatitis C Virus Reactivation in a Breast Cancer Patient Undergoing Chemotherapy. Chin Med J (Engl) 2017; 130:2015-2016. [PMID: 28776564 PMCID: PMC5555146 DOI: 10.4103/0366-6999.211876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Affiliation(s)
- Yu-Tuan Wu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Zhou Xu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Hao-Ran Chen
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Bilal Arshad
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Hong-Yuan Li
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Kai-Nan Wu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Ling-Quan Kong
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| |
Collapse
|
|
34
|
McCarthy MK, Morrison TE. Persistent RNA virus infections: do PAMPS drive chronic disease? Curr Opin Virol 2017; 23:8-15. [PMID: 28214732 PMCID: PMC5474173 DOI: 10.1016/j.coviro.2017.01.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 01/16/2017] [Accepted: 01/27/2017] [Indexed: 12/12/2022]
Abstract
Chronic disease associated with persistent RNA virus infections represents a key public health concern. While human immunodeficiency virus-1 and hepatitis C virus are perhaps the most well-known examples of persistent RNA viruses that cause chronic disease, evidence suggests that many other RNA viruses, including re-emerging viruses such as chikungunya virus, Ebola virus and Zika virus, establish persistent infections. The mechanisms by which RNA viruses drive chronic disease are poorly understood. Here, we discuss how the persistence of viral RNA may drive chronic disease manifestations via the activation of RNA sensing pathways.
Collapse
Affiliation(s)
- Mary K McCarthy
- Department of Immunology and Microbiology, University of Colorado School of Medicine, USA
| | - Thomas E Morrison
- Department of Immunology and Microbiology, University of Colorado School of Medicine, USA.
| |
Collapse
|
|
35
|
The viral innate immune antagonism and an alternative vaccine design for PRRS virus. Vet Microbiol 2017; 209:75-89. [PMID: 28341332 PMCID: PMC7111430 DOI: 10.1016/j.vetmic.2017.03.014] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 03/10/2017] [Accepted: 03/13/2017] [Indexed: 02/06/2023]
Abstract
PRRS virus has evolved to suppress the antiviral innate immunity during infection. Type I interferons are potent antiviral cytokines and function to stimulate the adaptive immune responses. Six viral proteins have been identified as interferon antagonists and characterized for their molecular actions. Interferon antagonism-negative viruses are attenuated and have been proven induce protective immunity. Interferon suppression-negative PRRS virus may serve as an alternative vaccine for PRRS. Porcine reproductive and respiratory syndrome (PRRS) remains one of the most economically significant diseases in the swine industry worldwide. The current vaccines are less satisfactory to confer protections from heterologous infections and long-term persistence, and the need for better vaccines are urgent. The immunological hallmarks in PRRSV-infected pigs include the unusually poor production of type I interferons (IFNs-α/β) and the aberrant and delayed adaptive immune responses, indicating that PRRSV has the ability to suppress both innate and adaptive immune responses in the host. Type I IFNs are the potent antiviral cytokines and recent studies reveal their pleiotropic functions in the priming of expansion and maturation of adaptive immunity. Thus, IFN antagonism-negative PRRSV is hypothesized to be attenuated and to build effective and broad- spectrum innate and adaptive immune responses in pigs. Such vaccines are promising alternatives to traditional vaccines for PRRSV.
Collapse
|
|
36
|
Koutsoudakis G, Pérez-Del-Pulgar S, Forns X. Occult Hepatitis C Virus Infection: Are We Digging Too Deep? Gastroenterology 2017; 152:472-474. [PMID: 28038930 DOI: 10.1053/j.gastro.2016.12.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- George Koutsoudakis
- Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| | - Sofía Pérez-Del-Pulgar
- Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.
| |
Collapse
|
|
37
|
Mulrooney-Cousins P, Michalak T. Molecular Testing in Hepatitis Virus Related Disease. DIAGNOSTIC MOLECULAR PATHOLOGY 2017:63-73. [DOI: 10.1016/b978-0-12-800886-7.00006-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
38
|
Kwo PY, Lacerda MA. After the Direct-acting Antivirals Are Gone, There Is Still Work to Be Done in the Liver. Gastroenterology 2016; 151:582-4. [PMID: 27590790 DOI: 10.1053/j.gastro.2016.08.045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Paul Y Kwo
- Gastroenterology/Hepatology Division, Indiana University Health, Indiana University School of Medicine, Indianapolis, Indiana.
| | - Marco A Lacerda
- Gastroenterology/Hepatology Division, Indiana University Health, Indiana University School of Medicine, Indianapolis, Indiana
| |
Collapse
|
|
39
|
Oyero OG, Toyama M, Mitsuhiro N, Onifade AA, Hidaka A, Okamoto M, Baba M. SELECTIVE INHIBITION OF HEPATITIS C VIRUS REPLICATION BY ALPHA-ZAM, A NIGELLA SATIVA SEED FORMULATION. AFRICAN JOURNAL OF TRADITIONAL, COMPLEMENTARY, AND ALTERNATIVE MEDICINES 2016; 13:144-148. [PMID: 28480371 PMCID: PMC5412185 DOI: 10.21010/ajtcam.v13i6.20] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Background: Hepatitis C virus (HCV) infection became curable because of the development of direct acting antivirals (DAAs). However, the high cost of DAAs has greatly impeded their potential impact on the treatment of HCV infection. As a result, hepatitis C will continue to cause substantial morbidity, and mortality among chronically infected individuals in low and middle income countries. Thus, urgent need exists for developing cheaper drugs available to hepatitis C patients in these countries. Materials and Methods: Alpha-zam, an indigenous herbal formulation from Nigella sativa seed, was examined for its anti-HCV activity and cytotoxicity in genotype 1b HCV replicon cells. The antiviral activity was determined by luciferase expression and viral RNA synthesis, while the cytotoxicity was assessed by viable cell number and glyceraldehyde-3-phosphate dehydrogenase RNA synthesis in the replicon cells. Results: Alpha-zam was found to be a selective inhibitor of HCV replication. The 50% effective dilution and 50% cytotoxic dilution of Alpha-zam were 761- and < 100-fold, respectively, in the subgenomic replicon cells LucNeo#2. Its selective inhibition of HCV was also confirmed by HCV RNA levels in LucNeo#2 and in the full-genome HCV replicon cells NNC#2 using real-time reverse transcriptase polymerase chain reaction. Furthermore, the anti-HCV activity of Alpha-zam was not due to the induction of interferon. Conclusion: Alpha-zam selectively inhibits HCV replication and therefore has potential for a novel antiviral agent against HCV infection.
Collapse
Affiliation(s)
- Olufunmilayo G Oyero
- Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Masaaki Toyama
- Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Kagoshima University, Kagoshima, Japan
| | - Naoki Mitsuhiro
- Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Kagoshima University, Kagoshima, Japan
| | | | - Akemi Hidaka
- Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Kagoshima University, Kagoshima, Japan
| | - Mika Okamoto
- Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Kagoshima University, Kagoshima, Japan
| | - Masanori Baba
- Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Kagoshima University, Kagoshima, Japan
| |
Collapse
|
|
40
|
Tagawa A, Ogawa T, Tetsuka S, Otsuka M, Hashimoto R, Kato H, Ando K, Tanabe H. Hepatitis C virus (HCV) reactivation during fingolimod treatment for relapsing and remitting multiple sclerosis. Mult Scler Relat Disord 2016; 9:155-7. [PMID: 27645365 DOI: 10.1016/j.msard.2016.08.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 08/01/2016] [Accepted: 08/04/2016] [Indexed: 11/17/2022]
Abstract
We here report a case involving a 38-year-old female with relapsing and remitting multiple sclerosis who developed reactivation of hepatitis C virus (HCV) during administration of fingolimod for 16 months. She had been previously treated for chronic hepatitis C with pegylated interferon and ribavirin, and kept an undetectable HCV-RNA state for more than 4 years before fingolimod starting. Although the increased risk for viral reactivation, for example of herpes zoster virus and varicella-zoster virus, during fingolimod treatment is known, this is, to our knowledge, the first case report of HCV reappearance.
Collapse
Affiliation(s)
- Asako Tagawa
- Departments of Neurology, International University of Health and Welfare Hospital, 537-3 Iguchi Nasushiobara City, Tochigi 329-2763, Japan.
| | - Tomoko Ogawa
- Departments of Neurology, International University of Health and Welfare Hospital, 537-3 Iguchi Nasushiobara City, Tochigi 329-2763, Japan
| | - Syuichi Tetsuka
- Departments of Neurology, International University of Health and Welfare Hospital, 537-3 Iguchi Nasushiobara City, Tochigi 329-2763, Japan
| | - Mieko Otsuka
- Departments of Neurology, International University of Health and Welfare Hospital, 537-3 Iguchi Nasushiobara City, Tochigi 329-2763, Japan
| | - Ritsuo Hashimoto
- Departments of Neurology, International University of Health and Welfare Hospital, 537-3 Iguchi Nasushiobara City, Tochigi 329-2763, Japan
| | - Hiroyuki Kato
- Departments of Neurology, International University of Health and Welfare Hospital, 537-3 Iguchi Nasushiobara City, Tochigi 329-2763, Japan
| | - Katsuyoshi Ando
- Departments of Gastroenterology, International University of Health and Welfare Hospital, 537-3, Iguchi Nasushiobara City, Tochigi 329-2763, Japan
| | - Hiroki Tanabe
- Departments of Gastroenterology, International University of Health and Welfare Hospital, 537-3, Iguchi Nasushiobara City, Tochigi 329-2763, Japan
| |
Collapse
|
|
41
|
How I treat hepatitis C virus infection in patients with hematologic malignancies. Blood 2016; 128:1449-57. [PMID: 27443290 DOI: 10.1182/blood-2016-05-718643] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 07/12/2016] [Indexed: 12/20/2022] Open
Abstract
Hepatitis C virus (HCV) infection is not uncommon in cancer patients. Over the past 5 years, treatment of chronic HCV infection in patients with hematologic malignancies has evolved rapidly as safe and effective direct-acting antivirals (DAAs) have become the standard-of-care treatment. Today, chronic HCV infection should not prevent a patient from receiving cancer therapy or participating in clinical trials of chemotherapy because most infected patients can achieve virologic cure. Elimination of HCV from infected cancer patients confers virologic, hepatic, and oncologic advantages. Similar to the optimal therapy for HCV-infected patients without cancer, the optimal therapy for HCV-infected patients with cancer is evolving rapidly. The choice of regimens with DAAs should be individualized after thorough assessment for potential hematologic toxic effects and drug-drug interactions. This study presents clinical scenarios of HCV-infected patients with hematologic malignancies, focusing on diagnosis, clinical and laboratory presentations, complications, and DAA therapy. An up-to-date treatment algorithm is presented.
Collapse
|
|
42
|
Tamori A, Murakami Y, Kubo S, Itami S, Uchida-Kobayashi S, Morikawa H, Enomoto M, Takemura S, Tanahashi T, Taguchi YH, Kawada N. MicroRNA expression in hepatocellular carcinoma after the eradication of chronic hepatitis virus C infection using interferon therapy. Hepatol Res 2016; 46:E26-35. [PMID: 25788219 DOI: 10.1111/hepr.12518] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 02/18/2015] [Accepted: 03/11/2015] [Indexed: 02/06/2023]
Abstract
AIM Hepatocellular carcinoma (HCC) develops in up to 5% of patients after the successful treatment of chronic hepatitis C virus (HCV) infection using interferon therapy. The aim of this study was to characterize miRNA expression in liver tissues from patients who achieved a sustained viral response (SVR). METHODS Seventy-one patients with resected HCC were enrolled into the present study: 61 HCC from patients with continuously infected HCV (HCV-HCC) and 10 from patients who had achieved SVR (SVR-HCC). We also included non-tumor tissues (SVR-NT) from four patients with SVR-HCC, and liver tissue (SVR-CH) from four SVR patients without HCC. Total RNA was extracted from liver samples. The miRNA expression patterns were analyzed using microarrays. In addition, target gene expression was quantified after miRNA overexpression in HEK293 cells. RESULTS We could discriminate between SVR-HCC and HCV-HCC with 75.36% accuracy using the expression pattern of six specific miRNA. The expression levels of 37 miRNA were significantly lower in HCV-HCC than in SVR-HCC, whereas the expression of 25 miRNA was significantly higher in HCV-HCC than SVR-HCC (P < 1.0E-05). The expression of thrombospondin 1 was regulated in an opposing manner by miR-30a-3p in SVR-HCC and HCV-HCC. In non-tumor tissues, the expression pattern of seven miRNA could distinguish between SVR-CH and SVR-NT with 87.50% accuracy. CONCLUSION Comprehensive miRNA expression analyses could not only differentiate between SVR-HCC and HCV-HCC but also forecast hepatocarcinogenesis after achieving SVR.
Collapse
Affiliation(s)
- Akihiro Tamori
- Department of Hepatology, Osaka City University Graduate School of Medicine
| | - Yoshiki Murakami
- Department of Hepatology, Osaka City University Graduate School of Medicine
| | - Shoji Kubo
- Department of Hepatobiliary Surgery, Osaka City University Graduate School of Medicine, Osaka
| | - Saori Itami
- Department of Hepatology, Osaka City University Graduate School of Medicine
| | | | - Hiroyasu Morikawa
- Department of Hepatology, Osaka City University Graduate School of Medicine
| | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine
| | - Shigekazu Takemura
- Department of Hepatobiliary Surgery, Osaka City University Graduate School of Medicine, Osaka
| | | | - Y-H Taguchi
- Department of Physics, Chuo University, Tokyo, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University Graduate School of Medicine
| |
Collapse
|
|
43
|
Bartolomé J, Castillo I, Quiroga JA, Carreño V. Interleukin-28B polymorphisms and interferon gamma inducible protein-10 serum levels in seronegative occult hepatitis C virus infection. J Med Virol 2016; 88:268-74. [PMID: 26147900 DOI: 10.1002/jmv.24322] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2015] [Indexed: 12/31/2022]
Abstract
Polymorphisms upstream interleukin (IL)-28B gene and serum levels of interferon gamma inducible protein-10 (IP-10) are associated with spontaneous and treatment-induced hepatitis C virus (HCV) clearance. Patients with seronegative occult HCV infection are anti-HCV and serum HCV-RNA negative but have viral RNA in liver and abnormal values of liver enzymes. We examined if the rs12979860 polymorphism of IL-28B and serum IP-10 levels differ between chronic and seronegative occult CV infection. IL-28B polymorphism was determined with allele specific TaqMan probes in total DNA isolated from peripheral blood mononuclear cells and IP-10 by an enzyme-linked immunosorbent assay in serum from 99 patients with seronegative occult HCV infection and 130 untreated patients with chronic hepatitis C. IL-28B genotypes were also determined in 54 healthy volunteers. Prevalence of the IL-28B CC genotype was significantly higher in seronegative occult HCV infection (52/99; 52.5%) than in chronic hepatitis C (32/130; 24.6%, P < 0.0001) or healthy controls (19/54: 32.5%, P = 0.039). Among patients with seronegative occult HCV infection, HCV-RNA load in liver was significantly lower in those with the IL-28B CC genotype than in those with CT + TT genotypes (2.8 × 10(5) ± 5.8 × 10(4) vs. 4.1 × 10(5) ± 5.9 × 10(4) copies/μg of total RNA respectively; P = 0.023). Mean serum IP-10 levels were significantly lower in patients with seronegative occult HCV infection than in patients with chronic hepatitis C (160.8 ± 17.9 vs. 288.7 ± 13.3 pg/ml respectively; P < 0.0001). These findings suggest that the host immune response plays an important role in seronegative occult HCV infection in comparison with chronic hepatitis C.
Collapse
Affiliation(s)
- Javier Bartolomé
- Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain
| | | | | | - Vicente Carreño
- Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain
| |
Collapse
|
|
44
|
Murira A, Lapierre P, Lamarre A. Evolution of the Humoral Response during HCV Infection: Theories on the Origin of Broadly Neutralizing Antibodies and Implications for Vaccine Design. Adv Immunol 2015; 129:55-107. [PMID: 26791858 DOI: 10.1016/bs.ai.2015.09.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Similar to human immunodeficiency virus (HIV)-1, vaccine-induced elicitation of broadly neutralizing (bNt) antibodies (Abs) is gaining traction as a key goal toward the eradication of the hepatitis C virus (HCV) pandemic. Previously, the significance of the Ab response against HCV was underappreciated given the prevailing evidence advancing the role of the cellular immune response in clearance and overall control of the infection. However, recent findings have driven growing interest in the humoral arm of the immune response and in particular the role of bNt responses due to their ability to confer protective immunity upon passive transfer in animal models. Nevertheless, the origin and development of bNt Abs is poorly understood and their occurrence is rare as well as delayed with emergence only observed in the chronic phase of infection. In this review, we characterize the interplay between the host immune response and HCV as it progresses from the acute to chronic phase of infection. In addition, we place these events in the context of current hypotheses on the origin of bNt Abs against the HIV-1, whose humoral immune response is better characterized. Based on the increasing significance of the humoral immune response against HCV, characterization of these events may be critical in understanding the development of the bNt responses and, thus, provide strategies toward effective vaccine design.
Collapse
Affiliation(s)
- Armstrong Murira
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
| | - Pascal Lapierre
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier, Laval, Quebec, Canada
| | - Alain Lamarre
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
| |
Collapse
|
|
45
|
Peripheral Blood Mononuclear Cell Gene Expression Remains Broadly Altered Years after Successful Interferon-Based Hepatitis C Virus Treatment. J Immunol Res 2015; 2015:958231. [PMID: 26568966 PMCID: PMC4629046 DOI: 10.1155/2015/958231] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 07/24/2015] [Accepted: 07/27/2015] [Indexed: 02/06/2023] Open
Abstract
Background. Inflammatory gene expression in peripheral blood mononuclear cells (PBMCs) is altered in chronic Hepatitis C Virus (HCV) infection. Duration of changes after pegylated interferon- (peg-IFN-) based HCV treatment is unclear. Methods. PBMC mRNA expression of 184 inflammatory response genes was analyzed (nCounter GX Human Inflammation Kit, Nanostring) from peg-IFN treatment nonresponders (NR, n = 18), sustained virologic responders (SVR, n = 22), and spontaneous clearers (SC, n = 15). Logistic regression was used for comparison. Results. Median time from last treatment was 2 and 2.7 years in SVR and NR, respectively (p = NS). Mean mRNA counts were significantly different for 42 and 29 genes comparing SVR to SC patients and NR to SC, respectively, and no genes comparing SVR to NR. Differential expression of 24 genes was significantly different in both SVR and NR groups compared to SC. Among these 24 acute and chronic inflammatory cascade genes, significant upregulation was noted for proinflammatory transcription regulators Fos, CEBPB, and MyD88 in SVR and NR compared to SC. HDAC4 was significantly downregulated in SVR and NR compared to the SC group. Conclusions. PBMC inflammatory gene expression patterns in SVR resemble NR more than SC patients. A generalized inflammatory response persists in PBMCs long after successful peg-IFN treatment for HCV infection.
Collapse
|
|
46
|
Chen AY, Hoare M, Shankar AN, Allison M, Alexander GJM, Michalak TI. Persistence of Hepatitis C Virus Traces after Spontaneous Resolution of Hepatitis C. PLoS One 2015; 10:e0140312. [PMID: 26473969 PMCID: PMC4608821 DOI: 10.1371/journal.pone.0140312] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2015] [Accepted: 09/24/2015] [Indexed: 12/22/2022] Open
Abstract
Hepatitis C virus (HCV) frequently causes chronic hepatitis, while spontaneous recovery from infection is infrequent. Persistence of HCV after self-limited (spontaneous) resolution of hepatitis C was rarely investigated. The current study aimed to assess incidence and robustness of HCV persistence after self-resolved hepatitis C in individuals with normal liver enzymes and undetectable virus by conventional tests. Applying high sensitivity HCV RNA detection approaches, we analyzed plasma and peripheral blood mononuclear cells (PBMC) from individuals with previous hepatitis C infection. Parallel plasma and PBMC from 24 such non-viraemic individuals followed for 0.3–14.4 (mean 6.4) years were examined. Additional samples from 9 of them were obtained 4.5–7.2 (mean 5.9) years later. RNA was extracted from 250 μl plasma and, if HCV negative, from ~5 ml after ultracentrifugation, and from ex vivo stimulated PBMC. PBMC with evidence of HCV replication from 4 individuals were treated with HCV protease inhibitor, telaprevir. HCV RNA was detected in 14/24 (58.3%) plasma and 11/23 (47.8%) PBMC obtained during the first collection. HCV RNA replicative strand was evident in 7/11 (63.6%) PBMC. Overall, 17/24 (70.8%) individuals carried HCV RNA at mean follow-up of 5.9 years. Samples collected 4.5–7.2 years later revealed HCV in 4/9 (44.4%) plasma and 5/9 (55.5%) PBMC, while 4 (80%) of these 5 PBMC demonstrated virus replicative strand. Overall, 6/9 (66.7%) individuals remained viraemic for up to 20.7 (mean 12.7) years. Telaprevir entirely eliminated HCV replication in the PBMC examined. In conclusion, our results indicate that HCV can persist long after spontaneous resolution of hepatitis C at levels undetectable by current testing. An apparently effective host immune response curtailing hepatitis appears insufficient to completely eliminate the virus. The long-term morbidity of asymptomatic HCV carriage should be examined even in individuals who achieve undetectable HCV by standard testing and their need for treatment should be assessed.
Collapse
Affiliation(s)
- Annie Y. Chen
- Molecular Virology and Hepatology Research Group, Faculty of Medicine, Memorial University, St. John’s, Newfoundland and Labrador, Canada
| | - Matthew Hoare
- Cancer Research UK Cambridge Institute, Cambridge, United Kingdom
- Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Arun N. Shankar
- Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Michael Allison
- Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | | | - Tomasz I. Michalak
- Molecular Virology and Hepatology Research Group, Faculty of Medicine, Memorial University, St. John’s, Newfoundland and Labrador, Canada
- * E-mail:
| |
Collapse
|
|
47
|
Bagaglio S, Uberti-Foppa C, Di Serio C, Trentini F, Andolina A, Hasson H, Messina E, Merli M, Porrino L, Lazzarin A, Morsica G. Dynamic of Mixed HCV Infection in Plasma and PBMC of HIV/HCV Patients Under Treatment With Peg-IFN/Ribavirin. Medicine (Baltimore) 2015; 94:e1876. [PMID: 26512601 PMCID: PMC4985415 DOI: 10.1097/md.0000000000001876] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Revised: 09/25/2015] [Accepted: 09/29/2015] [Indexed: 02/07/2023] Open
Abstract
The extent of mixed hepatitis C virus (HCV) genotype in different compartments (plasma and peripheral blood mononuclear cell, PBMC) and possible association with treatment efficacy in HIV/HCV coinfected patients remains to be unknown.The objective of this study was to elucidate the frequency of mixed genotype infection (MG), its profile in different compartments during anti-HCV treatment, and the possible influence of different genotypes on the response rate.The compartmentalization of HCV population was investigated by next-generation sequencing in 19 HIV/HCV coinfected patients under anti-HCV treatment with peginterferon/ribavirin (P-R). Ten individuals were nonresponder (NR) or relapser (RE) to P-R treatment and 9 had a sustained virological response (SVR).Eleven/nineteen (58%) patients had MG in plasma compartment. Ten or 12 patients infected by a difficult to treat genotype (DTG) 1 or 4 as dominant strain, had an MG, whereas only 1/7 individuals infected by easy to treat genotype (ETG) harbored a mixed genotype, P = 0.006. HCV-RNA was more frequently detected in PBMC of NR (10/10) than in those of SVR (5/9), P = 0.032. Mixed genotype infection was detected in 6/15 (40%) PBMC-positive cases and was not associated with P-R treatment response. By multivariate analysis, MG in plasma samples was the most important viral factor affecting the treatment response (P = 0.0237).Detection of MG in plasma of HIV/HCV coinfected patients seems to represent the major determinant of response to P-R treatment. This finding may have important clinical implication in light of the new therapeutic approach in HIV/HCV coinfected individuals suggesting that combination treatment with direct acting antivirals could be less effective in MG.
Collapse
Affiliation(s)
- Sabrina Bagaglio
- Infectious Diseases Department, Scientific Institute Ospedale San Raffaele, Via Stamira d'Ancona 20, 20127 Milan, Italy (SB, CU-F, AA, HH, EM, MM, AL, GM); Vita-Salute University Via Olgettina 58, 20132 Milan, Italy (SB, AL); University Centre for Statistics in the Biomedical Sciences (CUSSB) Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milan, Italy (CDS, FT); L. Bocconi University, Via R. Sarfatti 25, 20136 Milan, Italy (FT); Mol Med Spa, Via Olgettina 58, 20132 Milan, Italy (LP)
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Eslamifar A, Ramezani A, Ehteram H, Razeghi E, Ahmadi F, Amini M, Banifazl M, Etemadi G, Keyvani H, Bavand A, Aghakhani A. Occult hepatitis C virus infection in Iranian hemodialysis patients. J Nephropathol 2015; 4:116-20. [PMID: 26457258 PMCID: PMC4596295 DOI: 10.12860/jnp.2015.22] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 06/13/2015] [Indexed: 12/18/2022] Open
Abstract
Background: Occult hepatitis C virus (HCV) infection is defined as the presence of HCV-RNA in liver or peripheral blood mononuclear cells (PBMCs) in the absence of detectable hepatitis C antibody (anti-HCV) or HCV-RNA in the serum. Low concentrations of HCV-RNA may be detected in PBMCs of hemodialysis (HD) patients and this could have a great impact on the management of HD patients.
Objectives: The aim of this study was to detect the occult HCV infection in Iranian HD patients.
Patients and Methods: A total of 70 anti-HCV negative HD patients from three dialysis units in Tehran, Iran were included in this study. In these cases, presence of HCV-RNA in plasma samples was tested by reverse transcriptase-nested polymerase chain reaction (RT-nested PCR). In cases with negative anti-HCV and plasma HCV-RNA, genomic HCV-RNA was checked in PBMC specimens by RT-nested PCR.
Results: Seventy anti-HCV negative HD patients were enrolled in the study. 32.85% and 1.43% of cases had elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) respectively. 7.14% of patients had elevated levels of both ALT and AST. HCV-RNA was negative in plasma samples of all anti-HCV negative HD subjects. The genomic HCV-RNA was not detected in any PBMC samples of HD cases with negative anti-HCV and plasma HCV-RNA.
Conclusions: Occult HCV infection was not detected in our HD patients despite of elevated levels of liver enzymes in some participants. Further studies involving larger number of HD patients are required to elucidate the rate of occult HCV infection in HD cases.
Collapse
Affiliation(s)
- Ali Eslamifar
- Clinical Research Department, Pasteur Institute of Iran, Tehran, Iran
| | - Amitis Ramezani
- Clinical Research Department, Pasteur Institute of Iran, Tehran, Iran
| | - Hassan Ehteram
- Department of Pathology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Effat Razeghi
- Nephrology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Farrokhlagha Ahmadi
- Nephrology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Manouchehr Amini
- Nephrology Department, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Banifazl
- Iranian Society for Support of Patients with Infectious Diseases, Tehran, Iran
| | | | - Hossein Keyvani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | - Anahita Bavand
- Clinical Research Department, Pasteur Institute of Iran, Tehran, Iran
| | - Arezoo Aghakhani
- Clinical Research Department, Pasteur Institute of Iran, Tehran, Iran
| |
Collapse
|
|
49
|
Khalvati Fahlyani B, Behzad-Behbahani A, Taghavi SA, Farhadi A, Salehi S, Adibzadeh S, Aboualizadeh F, Alavi P, Nikouyan N, Okhovat MA, Ranjbaran R, Rafiei Dehbidi GR, Shakibzadeh A. Development of an In-House TaqMan Real Time RT-PCR Assay to Quantify Hepatitis C Virus RNA in Serum and Peripheral Blood Mononuclear Cells in Patients With Chronic Hepatitis C Virus Infection. HEPATITIS MONTHLY 2015; 15:e28895. [PMID: 26425128 PMCID: PMC4584366 DOI: 10.5812/hepatmon.28895] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Revised: 08/02/2015] [Accepted: 08/12/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Viral load measurements are commonly used to monitor HCV infection in patients with chronic diseases or determining the number of HCV-genomes in serum samples of patients after sustained virological response. However, in some patients, HCV viral load in serum samples is too low to be detected by PCR, especially after treatment. OBJECTIVES The aim of this study was to develop a highly specific, sensitive, and reproducible in-house quantitative PCR using specific primers and probe cited in highly conservative region of HCV genome that allows simultaneous detection of HCV genotypes 1 - 4. MATERIALS AND METHODS In this study, three sets of primer pairs and a TaqMan probe for amplification and detection of selected region within 5'-non-coding (5'NCR) of four HCV genotypes were used. Using plasmid containing 5'NCR region of HCV, standard curve, threshold, and threshold cycle (CT) values were determined. Real-time and nested PCR were performed on HCV genotypes 1 - 4 extracted from plasma and peripheral blood mononuclear cells (PBMCs) samples collected from patients with chronic HCV infection. RESULTS The lower limit detection of this in-house HCV real-time RT-PCR was determined as 100 RNA copies/mL. Inter- and intra-assay coefficient of variation (CV) of this in-house HCV real-time RT-PCR ranged from 0.9% to 1.8% and 1.76% to 3.94%, respectively. The viral load of the genotyped samples ranged from 2.0 × 10(6) ± 0.31 to 2.7 × 10(5) ± 0.46 copies/mL in serum samples and 5 × 10(2) ± 0.36 to 4.0 × 10(3) ± 0.51 copies/10(6) cells/mL of PBMCs. CONCLUSIONS The quite sensitive in-house TaqMan real time RT-PCR assay was able to detect and quantify all four main HCV genotypes prevailing around all geographical regions of Iran.
Collapse
Affiliation(s)
- Bahman Khalvati Fahlyani
- Diagnosis Laboratory Sciences and Technology Research Center, School of Paramedical, Sciences Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Abbas Behzad-Behbahani
- Diagnosis Laboratory Sciences and Technology Research Center, School of Paramedical, Sciences Shiraz University of Medical Sciences, Shiraz, IR Iran
- Department of Biotechnology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, IR Iran
- Corresponding Author: Abbas Behzad-Behbahani, Diagnosis Laboratory Sciences and Technology Research Center, School of Paramedical, Sciences Shiraz University of Medical Sciences, Shiraz, IR Iran. Tel: +98-7132270301, Fax: +98-7132270301, E-mail:
| | - Seiied Alireza Taghavi
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Ali Farhadi
- Diagnosis Laboratory Sciences and Technology Research Center, School of Paramedical, Sciences Shiraz University of Medical Sciences, Shiraz, IR Iran
- Department of Biotechnology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Saeede Salehi
- Diagnosis Laboratory Sciences and Technology Research Center, School of Paramedical, Sciences Shiraz University of Medical Sciences, Shiraz, IR Iran
- Department of Biotechnology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Setare Adibzadeh
- Diagnosis Laboratory Sciences and Technology Research Center, School of Paramedical, Sciences Shiraz University of Medical Sciences, Shiraz, IR Iran
- Department of Biotechnology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Farzaneh Aboualizadeh
- Diagnosis Laboratory Sciences and Technology Research Center, School of Paramedical, Sciences Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Parniyan Alavi
- Diagnosis Laboratory Sciences and Technology Research Center, School of Paramedical, Sciences Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Negin Nikouyan
- Diagnosis Laboratory Sciences and Technology Research Center, School of Paramedical, Sciences Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Mohammad Ali Okhovat
- Diagnosis Laboratory Sciences and Technology Research Center, School of Paramedical, Sciences Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Reza Ranjbaran
- Diagnosis Laboratory Sciences and Technology Research Center, School of Paramedical, Sciences Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Gholam Reza Rafiei Dehbidi
- Diagnosis Laboratory Sciences and Technology Research Center, School of Paramedical, Sciences Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Arash Shakibzadeh
- Diagnosis Laboratory Sciences and Technology Research Center, School of Paramedical, Sciences Shiraz University of Medical Sciences, Shiraz, IR Iran
| |
Collapse
|
|
50
|
Rivero-Juarez A, Caruz A, Real LM, Martinez-Dueñas L, Marquez FJ, Frias M, Recio E, Gordon A, Pineda JA, Rivero A, Camacho A. Longitudinal evaluation of hepatitis C viral persistence in HIV-infected patients with spontaneous hepatitis C clearance. Eur J Clin Microbiol Infect Dis 2015; 34:2171-5. [PMID: 26254560 DOI: 10.1007/s10096-015-2463-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 07/21/2015] [Indexed: 01/30/2023]
Abstract
Hepatitis C virus (HCV) viral persistence in patients with spontaneous viral clearance is controversial. Several studies have shown HCV-RNA in peripheral blood mononuclear cells (PBMCs) and/or liver tissue among patients who have cleared the virus spontaneously, suggesting that viral persistence is a common situation that could involve the entire population studied. Thus, our aim was to evaluate HCV-RNA persistence in PBMCs and hepatocytes in subjects infected with the human immunodeficiency virus (HIV). A total of 1508 patients were prospectively followed and tested for anti-HCV antibodies and HCV-RNA to identify the patients who achieved spontaneous viral clearance. In all of the patients, the persistence of HCV-RNA in PBMCs was evaluated longitudinally during 2 years of follow-up. Fifty-nine patients fulfilled the inclusion/exclusion criteria and were included in the study. HCV-RNA was not detected in the PBMCs at baseline [59 PBMCs samples tested; 0 %; 95 % confidence interval (CI): 0-3.3 %] or during the follow-up (147 PBMCs samples tested; 0 %; 95 % CI: 0-2.02 %). Our study shows that HCV viral persistence is not a frequent occurrence in HIV-infected patients who have spontaneously resolved an HCV infection. Thus, the lack of serum HCV-RNA should continue to be addressed as the standard of healing.
Collapse
Affiliation(s)
- A Rivero-Juarez
- Infectious Diseases Unit, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, Avd. Menéndez Pidal s/n, 14004, Córdoba, Spain
| | - A Caruz
- Immunogenetics Unit, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - L M Real
- Infectious Diseases Unit, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario de Valme, Sevilla, Spain
| | - L Martinez-Dueñas
- Infectious Diseases Unit, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, Avd. Menéndez Pidal s/n, 14004, Córdoba, Spain
| | - F J Marquez
- Immunogenetics Unit, Department of Experimental Biology, University of Jaen, Jaen, Spain
| | - M Frias
- Infectious Diseases Unit, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, Avd. Menéndez Pidal s/n, 14004, Córdoba, Spain
| | - E Recio
- Infectious Diseases Unit, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario de Valme, Sevilla, Spain
| | - A Gordon
- Infectious Diseases Unit, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, Avd. Menéndez Pidal s/n, 14004, Córdoba, Spain
| | - J A Pineda
- Infectious Diseases Unit, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario de Valme, Sevilla, Spain
| | - A Rivero
- Infectious Diseases Unit, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, Avd. Menéndez Pidal s/n, 14004, Córdoba, Spain.
| | - A Camacho
- Infectious Diseases Unit, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía de Córdoba, Avd. Menéndez Pidal s/n, 14004, Córdoba, Spain
| |
Collapse
|