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Designing an HCV vaccine: a unique convergence of prevention and therapy? Curr Opin Virol 2017; 23:113-119. [PMID: 28550816 DOI: 10.1016/j.coviro.2017.03.014] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 03/27/2017] [Indexed: 12/23/2022]
Abstract
Direct acting antivirals can cure chronic hepatitis C virus (HCV) infection but whether they will reduce global liver disease burden is uncertain. Most chronic infections are undiagnosed and transmission has increased in recent years. The first trial of a preventive vaccine is now underway in humans at risk for HCV infection. It will test the novel hypothesis that T cell-mediated immunity alone can prevent persistent HCV infection. Another vaccine that elicits neutralizing antibodies is at an advanced stage of development. Attention is turning to the understudied question of whether direct acting antiviral (DAA) cure of chronic infection restores HCV immunity. If not, it will be important to determine if preventive vaccines can also act therapeutically to reverse immune dysfunction and protect from re-infection.
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2
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Rosen HR. "Hep C, where art thou": What are the remaining (fundable) questions in hepatitis C virus research? Hepatology 2017; 65:341-349. [PMID: 27640881 DOI: 10.1002/hep.28848] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 09/09/2016] [Indexed: 12/18/2022]
Abstract
Hepatitis C virus (HCV) has dominated the field of hepatology for the past 25 years, and its cure in the majority of treated patients is one of the greatest achievements in all of medicine. However, the latter has led to the belief by some that HCV research should be shelved for other, more pressing areas. The mission for HCV eradication is far from accomplished. As a historical reference, we should consider that disease elimination has required vaccination with all previously controlled infections including smallpox and polio and that simple, effective treatment is not sufficient in most infections to lead to substantial control. Syphilis is the best example, for which a single dose of penicillin (which literally costs pennies and that we have had since 1945) is curative in early stages. Not only have we not eradicated syphilis, rates of infection have increased in many places within the United States in recent years. Most HCV-infected subjects are unaware of their infection, remaining at risk for transmission to others and disease progression, including cirrhosis and hepatocellular carcinoma. In the era of highly effective direct-acting antivirals (DAAs), many questions pertaining to HCV remain, but they are more complex and difficult to answer. Here, I provide my perspective on some of these salient issues: the residual risk for disease progression after sustained virologic response, the optimal approach to current DAA failures, the impact of targeting people who inject drugs with DAAs, vaccine prospects, and application of neutralizing HCV glycoprotein antibodies. (Hepatology 2017;65:341-349).
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Affiliation(s)
- Hugo Ramón Rosen
- Division of Gastroenterology and Hepatology (B-158), Department of Medicine, University of Colorado Health Sciences Center, Aurora, CO
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3
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Wyles D, Lin J. Clinical Manifestations of Acute and Chronic Hepatitis. Infect Dis (Lond) 2017. [DOI: 10.1016/b978-0-7020-6285-8.00042-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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4
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Progress towards a hepatitis C virus vaccine. Emerg Microbes Infect 2013; 2:e79. [PMID: 26038445 PMCID: PMC3924556 DOI: 10.1038/emi.2013.79] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 10/01/2013] [Accepted: 10/09/2013] [Indexed: 12/16/2022]
Abstract
New drugs to treat hepatitis C are expected to be approved over the next few years which promise to cure nearly all patients. However, due to issues of expected drug resistance, suboptimal activity against diverse hepatitis C virus (HCV) genotypes and especially because of their extremely high cost, it is unlikely that these HCV drugs will substantially reduce the world's HCV carrier population of around 170 million in the near future or the estimated global incidence of millions of new HCV infections. For these reasons, there is an urgent need to develop a prophylactic HCV vaccine and also to determine if therapeutic vaccines can aid in the treatment of chronically infected patients. After much early pessimism on the prospects for an effective prophylactic HCV vaccine, our recent knowledge of immune correlates of protection combined with the demonstrated immunogenicity and protective animal efficacies of various HCV vaccine candidates now allows for realistic optimism. This review summarizes the current rationale and status of clinical and experimental HCV vaccine candidates based on the elicitation of cross-neutralizing antibodies and broad cellular immune responses to this highly diverse virus.
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5
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Abstract
Since the discovery of hepatitis C virus (HCV) by molecular cloning almost a quarter of a century ago, unprecedented at the time because the virus had never been grown in cell culture or detected serologically, there have been impressive strides in many facets of our understanding of the natural history of the disease, the viral life cycle, the pathogenesis, and antiviral therapy. It is apparent that the virus has developed multiple strategies to evade immune surveillance and eradication. This Review covers what we currently understand of the temporal and spatial immunological changes within the human innate and adaptive host immune responses that ultimately determine the outcomes of HCV infection.
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6
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Liang TJ. Current progress in development of hepatitis C virus vaccines. Nat Med 2013; 19:869-78. [PMID: 23836237 PMCID: PMC6263146 DOI: 10.1038/nm.3183] [Citation(s) in RCA: 127] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 02/22/2013] [Indexed: 12/14/2022]
Abstract
Despite major advances in the understanding and treatment of hepatitis C, a preventive vaccine remains elusive. The marked genetic diversity and multiple mechanisms of persistence of hepatitis C virus, combined with the relatively poor immune response of the infected host against the virus, are major barriers. The lack of robust and convenient model systems further hampers the effort to develop an effective vaccine. Advances in our understanding of virus-host interactions and protective immunity in hepatitis C virus infection provide an important roadmap to develop potent and broadly directed vaccine candidates targeting both humoral and cellular immune responses. Multiple approaches to generating and testing viral immunogens have met with variable success. Several candidates have advanced to clinical trials based on promising results in chimpanzees. The ultimate path to a successful preventive vaccine requires comprehensive evaluations of all aspects of protective immunity, innovative application of state-of-the-art vaccine technology and properly designed vaccine trials that can affirm definitive endpoints of efficacy.
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Affiliation(s)
- T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
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7
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Abstract
Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatocellular carcinoma worldwide. Due to shared transmission routes, the prevalence of HCV is especially high among individuals infected with HIV. HIV uninfected individuals spontaneously clear HCV approximately 30 % of the time, while the rate of control in HIV infected individuals who subsequently acquire HCV is substantially lower. In addition, complications of HCV are more frequent in those with HIV infection, making liver disease the leading cause of non-AIDS-related death in HIV infected individuals. This review summarizes recent advances in understanding the role of the innate and adaptive immune responses to HCV in those with and without HIV. Further defining the interaction between hepatitis C and the host immune system will potentially reveal insights into HCV pathogenesis and the host's ability to prevent persistent infection, as well as direct the development of vaccines.
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Affiliation(s)
- Rebecca R Terilli
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Rangos Building, Suite 536, 855 N Wolfe St, Baltimore, MD 21205, USA
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8
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Hepatitis C vaccines. Vaccines (Basel) 2013. [DOI: 10.1016/b978-1-4557-0090-5.00051-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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9
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Alvarez-Lajonchere L, Dueñas-Carrera S. Complete definition of immunological correlates of protection and clearance of hepatitis C virus infection: a relevant pending task for vaccine development. Int Rev Immunol 2012; 31:223-42. [PMID: 22587022 DOI: 10.3109/08830185.2012.680552] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Hepatitis C virus (HCV) infects approximately 3% of global population. This pathogen is one of the main causes of chronic viral hepatitis, cirrhosis, and liver cancer, as well as the principal reason for liver transplant in Western countries. Therapy against HCV infection is effective in only half of treated patients. There is no vaccine available against HCV. Some vaccine candidates have reached the clinical trials but several factors, including the incomplete definition of immunological correlates of protection and treatment-related clearance have slowed down vaccine development. Precisely, the present review discusses the state of the art in the establishment of parameters related with immunity against HCV. Validity and limitations of the information accumulated from chimpanzees and other animal models, analysis of studies in humans infected with HCV, and relevance of aspects like type, strength, duration, and specificity of immune response related to successful outcome are evaluated in detail. Moreover, the immune responses induced in some clinical trials with vaccine candidates resemble the theoretical immunological correlates, raising questions about the validity of those correlates. When all facts are taken together, complete definition of immunological correlates for protection or treatment-related clearance is an urgent priority. A limited or wrong criterion with respect to this relevant matter might cause incorrect vaccine design and selection of immunization strategies or erroneous clinical evaluation.
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Schmidt J, Thimme R, Neumann-Haefelin C. Host genetics in immune-mediated hepatitis C virus clearance. Biomark Med 2011; 5:155-69. [PMID: 21473719 DOI: 10.2217/bmm.11.19] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Upon infection with hepatitis C virus (HCV), only few patients spontaneously clear the virus, while most patients develop chronic HCV infection. The host innate and adaptive immune response is believed to be the key determinant of viral clearance or persistence. Several host factors have been demonstrated to influence the efficiency of the antiviral immune response, including IL-28B polymorphisms, inhibitory natural killer cell receptors, as well as HLA class I and II alleles presenting viral antigens to CD8(+) and CD4(+) T cells. The understanding of the respective mechanisms is essential for the development of successful vaccination strategies against HCV.
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Affiliation(s)
- Julia Schmidt
- Department of Medicine II, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany
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11
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Abstract
The hepatitis C virus (HCV) is a global public health problem affecting approximately 2% of the human population. The majority of HCV infections (more than 70%) result in life-long persistence of the virus that substantially increases the risk of serious liver diseases, including cirrhosis and hepatocellular carcinoma. The remainder (less than 30%) resolves spontaneously, often resulting in long-lived protection from persistence upon reexposure to the virus. To persist, the virus must replicate and this requires effective evasion of adaptive immune responses. In this review, the role of humoral and cellular immunity in preventing HCV persistence, and the mechanisms used by the virus to subvert protective host responses, are considered.
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12
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Abstract
Common variable immunodeficiency (CVID) is not a homogeneous disease, as has become clear from recent scientific studies. This makes the interpretation of studies of clinical therapeutics difficult to assess and raises questions about historical case reports. The evidence for the optimum use of replacement immunoglobulin in CVID is reviewed. This therapy represents the current gold standard, despite attempts to use other immunostimulatory compounds. Questions of product properties, product selection, adverse events and infectious risks are addressed. Products are not interchangeable and have different physicochemical characteristics. Despite intravenous immunoglobulin being in use for 20 years, there are still unanswered questions over dose and target trough IgG levels, particularly with respect to patients with established lung disease. The management of organ-based complications of CVID is discussed. This includes the treatment of unusual infections such as mycoplasmas and enteroviruses, which are specific to antibody deficiency. The diagnosis and treatment of the granulomatous disease of CVID is discussed. The role of surgery, including lung transplantation, in the management of CVID complications is reviewed. There are few available data on optimum strategies for antibiotic usage for bacterial infective complications and it is clear that present regimens, at least in severe recurrent sinus disease, are not consistently effective. Better clinical trials are required to identify appropriate regimens and validate or disprove widely held assumptions about therapy in CVID. Despite advances in diagnosis and management, there is abundant evidence in the UK that patients do not yet receive rapid diagnosis and optimum therapy, even within the limited published data currently available. This leads to considerable avoidable morbidity and mortality.
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Affiliation(s)
- C A Bethune
- Regional Department of Immunology, Royal Victoria Infirmary, Newcastle upon Tyne, England
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Nielsen SU, Bassendine MF, Martin C, Lowther D, Purcell PJ, King BJ, Neely D, Toms GL. Characterization of hepatitis C RNA-containing particles from human liver by density and size. J Gen Virol 2008; 89:2507-2517. [PMID: 18796720 PMCID: PMC2557069 DOI: 10.1099/vir.0.2008/000083-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) particles found in vivo are heterogeneous in density and size, but their detailed characterization has been restricted by the low titre of HCV in human serum. Previously, our group has found that HCV circulates in blood in association with very-low-density lipoprotein (VLDL). Our aim in this study was to characterize HCV RNA-containing membranes and particles in human liver by both density and size and to identify the subcellular compartment(s) where the association with VLDL occurs. HCV was purified by density using iodixanol gradients and by size using gel filtration. Both positive-strand HCV RNA (present in virus particles) and negative-strand HCV RNA (an intermediate in virus replication) were found with densities below 1.08 g ml−1. Viral structural and non-structural proteins, host proteins ApoB, ApoE and caveolin-2, as well as cholesterol, triglyceride and phospholipids were also detected in these low density fractions. After fractionation by size with Superose gel filtration, HCV RNA and viral proteins co-fractionated with endoplasmic reticulum proteins and VLDL. Fractionation on Toyopearl, which separates particles with diameters up to 200 nm, showed that 78 % of HCV RNA from liver was >100 nm in size, with a positive-/negative-strand ratio of 6 : 1. Also, 8 % of HCV RNA was found in particles with diameters between 40 nm and 70 nm and a positive-/negative-strand ratio of 45 : 1. This HCV was associated with ApoB, ApoE and viral glycoprotein E2, similar to viral particles circulating in serum. Our results indicate that the association between HCV and VLDL occurs in the liver.
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Affiliation(s)
- Søren U Nielsen
- Liver Research Group, Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Margaret F Bassendine
- Liver Research Group, Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Caroline Martin
- Liver Research Group, Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Daniel Lowther
- Liver Research Group, Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Paul J Purcell
- Liver Research Group, Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Barnabas J King
- Liver Research Group, Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Dermot Neely
- Department of Clinical Biochemistry, Royal Victoria Infirmary, Newcastle upon Tyne, UK
| | - Geoffrey L Toms
- Liver Research Group, Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
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14
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Zeisel MB, Cosset FL, Baumert TF. Host neutralizing responses and pathogenesis of hepatitis C virus infection. Hepatology 2008; 48:299-307. [PMID: 18508291 DOI: 10.1002/hep.22307] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Fafi-Kremer S, Zeisel MB, Schvoerer E, Soulier E, Habersetzer F, Wolf P, Doffoel M, Baumert TF, Stoll-Keller F. [Neutralizing antibodies in hepatitis C virus infection]. ACTA ACUST UNITED AC 2008; 32:491-8. [PMID: 18467058 DOI: 10.1016/j.gcb.2008.02.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2007] [Revised: 01/29/2008] [Accepted: 02/29/2008] [Indexed: 01/12/2023]
Abstract
Hepatitis C virus (HCV) results in persistent infection in more than 70% of infected individuals despite the development of humoral and cellular immune responses. Following infection, although antibodies targeting epitopes of both structural and non structural proteins are elicited, the virus evades antibody-mediated neutralization. Studies of host neutralizing responses against HCV have been limited by the lack of a convenient tissue culture system for HCV infection. In the past five years in vitro models have been developed to characterize interaction of HCV glycoproteins with host cell entry factors and detect antibodies interfering with HCV entry and infection. These models have been used to characterize targets of neutralizing responses and better understand their impact on the pathogenesis of infection.
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Affiliation(s)
- S Fafi-Kremer
- Laboratoire de virologie, Inserm U748, 3, rue Koeberlé, 67000 Strasbourg, France
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16
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17
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Zeisel MB, Fafi-Kremer S, Fofana I, Barth H, Stoll-Keller F, Doffoel M, Baumert TF. Neutralizing antibodies in hepatitis C virus infection. World J Gastroenterol 2007; 13:4824-30. [PMID: 17828813 PMCID: PMC4611760 DOI: 10.3748/wjg.v13.i36.4824] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a major cause of hepatitis world-wide. The majority of infected individuals develop chronic hepatitis which can then progress to liver cirrhosis and hepatocellular carcinoma. Spontaneous viral clearance occurs in about 20%-30% of acutely infected individuals and results in resolution of infection without sequaelae. Both viral and host factors appear to play an important role for resolution of acute infection. A large body of evidence suggests that a strong, multispecific and long-lasting cellular immune response appears to be important for control of viral infection in acute hepatitis C. Due too the lack of convenient neutralization assays, the impact of neutralizing responses for control of viral infection had been less defined. In recent years, the development of robust tissue culture model systems for HCV entry and infection has finally allowed study of antibody-mediated neutralization and to gain further insights into viral targets of host neutralizing responses. In addition, detailed analysis of antibody-mediated neutralization in individual patients as well as cohorts with well defined viral isolates has enabled the study of neutralizing responses in the course of HCV infection and characterization of the impact of neutralizing antibodies for control of viral infection. This review will summarize recent progress in the understanding of the molecular mechanisms of antibody-mediated neutralization and its impact for HCV pathogenesis.
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Affiliation(s)
- Mirjam-B Zeisel
- Inserm Unite 748, Universite Louis Pasteur, 3 Rue Koeberle, Strasbourg F-67000, France
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18
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Hepatitis C virus envelope glycoprotein immunization of rodents elicits cross-reactive neutralizing antibodies. Vaccine 2007; 25:7773-84. [PMID: 17919789 DOI: 10.1016/j.vaccine.2007.08.053] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2007] [Revised: 08/14/2007] [Accepted: 08/26/2007] [Indexed: 01/01/2023]
Abstract
Neutralizing antibody responses elicited during infection generally confer protection from infection. Hepatitis C virus (HCV) encodes two glycoproteins E1 and E2 that are essential for virus entry and are the major target for neutralizing antibodies. To assess whether both glycoproteins are required for the generation of a neutralizing antibody response, rodents were immunized with a series of glycoproteins comprising full length and truncated versions. Guinea pigs immunized with HCV-1 genotype 1a E1E2p7, E1E2 or E2 generated high titer anti-glycoprotein antibody responses that neutralized the infectivity of HCVpp and HCVcc expressing gps of the same genotype as the immunizing antigen. Less potent neutralization of viruses bearing the genotype 2 strain J6 gps was observed. In contrast, immunized mice demonstrated reduced anti-gp antibody responses, consistent with their minimal neutralizing activity. Immunization with E2 alone was sufficient to induce a high titer response that neutralized HCV pseudoparticles (HCVpp) bearing diverse glycoproteins and cell culture grown HCV (HCVcc). The neutralization titer was reduced 3-fold by the presence of lipoproteins in human sera. Cross-competition of the guinea pig anti-E1E2 immune sera with a panel of epitope mapped anti-E2 monoclonal antibodies for binding E2 identified a series of epitopes within the N-terminal domain that may be immunogenic in the immunized rodents. These data demonstrate that recombinant E2 and E1E2 can induce polyclonal antibody responses with cross-reactive neutralizing activity, supporting the future development of prophylactic and therapeutic vaccines.
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Abstract
With an estimated 170 million infected individuals, hepatitis C virus (HCV) has a major impact on public health. A vaccine protecting against HCV infection is not available, and current antiviral therapies are characterized by limited efficacy, high costs, and substantial side effects. Binding of the virus to the cell surface followed by viral entry is the first step in a cascade of interactions between virus and the target cell that is required for the initiation of infection. Because this step represents a critical determinant of tissue tropism and pathogenesis, it is a major target for host cell responses such as antibody-mediated virus-neutralization-and a promising target for new antiviral therapy. The recent development of novel tissue culture model systems for the study of the first steps of HCV infection has allowed rapid progress in the understanding of the molecular mechanisms of HCV binding and entry. This review summarizes the impact of recently identified viral and host cell factors for HCV attachment and entry. Clinical implications of this important process for the pathogenesis of HCV infection and novel therapeutic interventions are discussed.
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Affiliation(s)
- Heidi Barth
- Department of Medicine II, University of Freiburg, Freiburg, Germany
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Semmo N, Lucas M, Krashias G, Lauer G, Chapel H, Klenerman P. Maintenance of HCV-specific T-cell responses in antibody-deficient patients a decade after early therapy. Blood 2006; 107:4570-1. [PMID: 16717132 DOI: 10.1182/blood-2005-11-4522] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
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Abstract
KEY POINTS Intravenous immunoglobulins (IVIg) are preparations of normal human IgG obtained from large pools of healthy blood donors. IVIg can be used at low doses to treat patients with primary or secondary immune deficiencies and at high doses as an immunomodulatory agent in many autoimmune and systemic inflammatory diseases, especially hematologic and neurologic diseases. Its mechanisms of action are multiple, complex, and not yet well elucidated. Adverse effects are only rarely associated with IVIg. They are well tolerated, and the risk of transmission of infectious agents appears only theoretical.
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Affiliation(s)
- L Mouthon
- Université Paris-Descartes, Groupe hospitalier Cochin-Saint Vincent-de-Paul, Service de médecine interne, Centre de référence vascularites et sclérodermies, AP-HP, 27 rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14(75), France.
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Sundström S, Ota S, Dimberg LY, Masucci MG, Bergqvist A. Hepatitis C virus core protein induces an anergic state characterized by decreased interleukin-2 production and perturbation of mitogen-activated protein kinase responses. J Virol 2005; 79:2230-9. [PMID: 15681425 PMCID: PMC546561 DOI: 10.1128/jvi.79.4.2230-2239.2005] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Alterations of cytokine responses are thought to favor the establishment of persistent hepatitis C virus (HCV) infections, enhancing the risk of liver cirrhosis and hepatocellular carcinoma. Here we demonstrate that the expression of the HCV core (C) protein in stably transfected T cells correlates with a selective reduction of interleukin-2 (IL-2) promoter activity and IL-2 production in response to T-cell receptor triggering, whereas the activation of IL-4, IL-10, gamma interferon, and tumor necrosis factor alpha was moderately increased. This altered cytokine expression profile was associated with a perturbation of mitogen-activated protein (MAP) kinase responses. Extracellular regulated kinase and p38 were constitutively phosphorylated in C-expressing cells, while triggering of the costimulatory c-Jun N-terminal kinase (JNK) signaling cascade and activation of the CD28 response element within the IL-2 promoter appeared to be impaired. The perturbations of MAP kinase phosphorylation could be eliminated by cyclosporine A-mediated inhibition of nuclear factor of activated T cells, suggesting that the inactivation of JNK signaling and hyporesponsiveness to IL-2 induction were downstream consequences of C-induced Ca(2+) flux in a manner that mimics the induction of clonal anergy.
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Affiliation(s)
- Sara Sundström
- Microbiology and Tumor Biology Centre, Karolinska Institutet, SE-171 77 Stockholm, Sweden
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Lavillette D, Morice Y, Germanidis G, Donot P, Soulier A, Pagkalos E, Sakellariou G, Intrator L, Bartosch B, Pawlotsky JM, Cosset FL. Human serum facilitates hepatitis C virus infection, and neutralizing responses inversely correlate with viral replication kinetics at the acute phase of hepatitis C virus infection. J Virol 2005; 79:6023-34. [PMID: 15857988 PMCID: PMC1091689 DOI: 10.1128/jvi.79.10.6023-6034.2005] [Citation(s) in RCA: 209] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The factors leading to spontaneous clearance of hepatitis C virus (HCV) or to viral persistence are elusive. Understanding virus-host interactions that enable acute HCV clearance is key to the development of more effective therapeutic and prophylactic strategies. Here, using a sensitive neutralization assay based on infectious HCV pseudoparticles (HCVpp), we have studied the kinetics of humoral responses in a cohort of acute-phase patients infected during a single nosocomial outbreak in a hemodialysis center. The 17 patients were monitored for the spontaneous outcome of HCV infection for 6 months before a treatment decision was made. Blood samples were taken frequently (15 +/- 4 per patient). Phylogenetic analysis of the predominant virus(es) revealed infection by only one of two genotype 1b strains. While all patients seroconverted, their sera induced two opposing effects in HCVpp infection assays: inhibition and facilitation. Furthermore, the ability of sera to facilitate or inhibit infection correlated with the presence of either infecting HCV strain and divided the patients into two groups. In group 1, the progressive emergence of a relatively strong neutralizing response correlated with a fluctuating decrease in high initial viremia, leading to control of viral replication. Patients in group 2 failed to reduce viremia within the acute phase, and no neutralizing responses were detected despite seroconversion. Strikingly, sera of group 2, as well as naive sera, facilitated infection by HCVpp displaying HCV glycoproteins from different genotypes and strains, including those retrieved from patients. These results provide new insights into the mechanisms of viral persistence and immune control of viremia.
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Michels H, Burmester GR, Buttgereit F. [Intravenous immunoglobulins in chronic idiopathic myositis]. Z Rheumatol 2005; 64:102-10. [PMID: 15793676 DOI: 10.1007/s00393-005-0695-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- H Michels
- Rheumaklinik für Kinder und Jugendliche, Gehfeldstr. 24, 82467 Garmisch-Partenkirchen, Germany.
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25
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Spada E, Sagliocca L, Sourdis J, Garbuglia AR, Poggi V, De Fusco C, Mele A. Use of the minimum spanning tree model for molecular epidemiological investigation of a nosocomial outbreak of hepatitis C virus infection. J Clin Microbiol 2004; 42:4230-6. [PMID: 15365016 PMCID: PMC516344 DOI: 10.1128/jcm.42.9.4230-4236.2004] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The minimum spanning tree (MST) model was applied to identify the history of transmission of hepatitis C virus (HCV) infection in an outbreak involving five children attending a pediatric oncology-hematology outpatient ward between 1992 and 2000. We collected blood samples from all children attending since 1992, all household contacts, and one health care worker positive for antibody to HCV (anti-HCV). HCV RNA detection was performed with these samples and with smears of routinely collected bone marrow samples. For all isolates, we performed sequence analysis and phylogenetic tree analysis of hypervariable region 1 of the E2 gene. The MST model was applied to clinical-epidemiological and molecular data. No additional cases were detected. All children, but not the health care worker, showed genotype 3a. On six occasions, all but one child had shared the medication room with another patient who later seroconverted. HCV RNA detection in bone marrow smears revealed, in some cases, a delay of several months in anti-HCV responses. Sequence analysis and phylogenetic tree analysis revealed a high identity among the isolates. The MST model applied to molecular data, together with the clinical-epidemiological data, allowed us to identify the source of the outbreak and the most probable patient-to-patient chain of transmission. The management of central venous catheters was suspected to be the probable route of transmission. In conclusion, the MST model, supported by an exhaustive clinical-epidemiological investigation, appears to be a useful tool in tracing the history of transmission in outbreaks of HCV infection.
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Affiliation(s)
- Enea Spada
- Istituto Superiore di Sanità, National Center of Epidemiology, Surveillance, and Health Promotion, Clinical Epidemiology Unit, Via. Regina Elena 299, 00161 Rome, Italy.
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26
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27
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Logvinoff C, Major ME, Oldach D, Heyward S, Talal A, Balfe P, Feinstone SM, Alter H, Rice CM, McKeating JA. Neutralizing antibody response during acute and chronic hepatitis C virus infection. Proc Natl Acad Sci U S A 2004; 101:10149-54. [PMID: 15220475 PMCID: PMC454180 DOI: 10.1073/pnas.0403519101] [Citation(s) in RCA: 328] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Little is known about the role of Abs in determining the outcome of hepatitis C virus (HCV) infection. By using infectious retroviral pseudotypes bearing HCV glycoproteins, we measured neutralizing Ab (nAb) responses during acute and chronic HCV infection. In seven acutely infected health care workers, only two developed a nAb response that failed to associate with viral clearance. In contrast, the majority of chronically infected patients had nAbs. To determine the kinetics of strain-specific and crossreactive nAb emergence, we studied patient H, the source of the prototype genotype 1a H77 HCV strain. An early weak nAb response, specific for the autologous virus, was detected at seroconversion. However, neutralization of heterologous viruses was detected only between 33 and 111 weeks of infection. We also examined the development of nAbs in 10 chimpanzees infected with H77 clonal virus. No nAb responses were detected in three animals that cleared virus, whereas strain-specific nAbs were detected in six of the seven chronically infected animals after approximately 50 weeks of infection. The delayed appearance of high titer crossreactive nAbs in chronically infected patients suggests that selective mechanism(s) may operate to prevent the appearance of these Abs during acute infection. The long-term persistence of these nAbs in chronically infected patients may regulate viral replication.
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Affiliation(s)
- C Logvinoff
- Center for the Study of Hepatitis C, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA
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28
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Nielsen SU, Bassendine MF, Burt AD, Bevitt DJ, Toms GL. Characterization of the genome and structural proteins of hepatitis C virus resolved from infected human liver. J Gen Virol 2004; 85:1497-1507. [PMID: 15166434 PMCID: PMC1810391 DOI: 10.1099/vir.0.79967-0] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
In the absence of satisfactory cell culture systems for hepatitis C virus (HCV), virtually all that is known about the proteins of the virus has been learned by the study of recombinant proteins. Characterization of virus proteins from patients with HCV has been retarded by the low virus titre in blood and limited availability of infected tissue. Here, the authors have identified a primary infection in a liver transplanted into an immunodeficient patient with chronic HCV. The patient required re-transplant and the infected liver, removed 6 weeks after the initial transplant, had a very high titre of HCV, 5 x 10(9) International Units (IU) per gram of liver. The density distribution of HCV in iodixanol gradients showed a peak at 1.04 g x ml(-1) with 73 % of virus below 1.08 g x ml(-1). Full-length HCV RNA was detected by Northern blotting and the ratio between positive- and negative-strand HCV RNA was determined as 60. HCV was partially purified by precipitation with heparin/Mn(2+) and a single species of each of the three structural proteins, core, E1 and E2, was detected by Western blotting. The molecular mass of core was 20 kDa, which corresponds to the mature form from recombinant sources. The molecular mass of glycoprotein E1 was 31 kDa before and 21 kDa after deglycosylation with PNGase F or endoglycosidase H. Glycoprotein E2 was 62 kDa before and 36 kDa after deglycosylation, but E2-P7 was not detected. This was in contrast to recombinant sources of E2 which contain E2-P7.
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Affiliation(s)
- Søren U. Nielsen
- School of Clinical Medical Sciences, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
| | - Margaret F. Bassendine
- School of Clinical Medical Sciences, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
| | - Alastair D. Burt
- School of Clinical Medical Sciences, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
- School of Clinical and Laboratory Sciences, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
| | - Debra J. Bevitt
- School of Clinical Medical Sciences, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
| | - Geoffrey L. Toms
- School of Clinical Medical Sciences, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
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29
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Abstract
1. The development of hepatitis C virus (HCV) quasispecies has a number of biological consequences, including the development of escape mutants to humoral or cellular immunity, the generation of "defective" viral particles, variable cell tropism, and the development of drug resistance. 2. Accumulating evidence shows that HCV affects the early innate immune response mediated by natural killer and dendritic cells. 3. Recent data suggest that clearance of HCV bestows antibody to HCV immunity that affords partial protection against persistent infection. However, after spontaneous recovery from HCV infection, titers of HCV-specific antibodies decline and disappear in a subset of patients, whereas viral-specific CD4(+) and CD8(+) T-cell responses persist for decades. 4. HCV-specific CD8(+) T-cell responses are phenotypically and functionally diverse and may be associated with either viral eradication or chronic hepatic immunopathologic states. 5. Novel HCV genome-wide screening approaches have shown that the breadth of the immune response is considerably greater than was initially appreciated using more conventional assays, but why the majority of patients remain chronically infected despite the presence of viral-specific immune responses remains undefined.
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Affiliation(s)
- Hugo R Rosen
- Division of Gastroenterology/Hepatology, Portland Veterans Affairs Medical Center, Portland, OR 97207, USA.
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30
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Affiliation(s)
- Alfredo Alberti
- Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani 2, 35100 Padova, Italy.
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31
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Henderson DK. Managing occupational risks for hepatitis C transmission in the health care setting. Clin Microbiol Rev 2003; 16:546-68. [PMID: 12857782 PMCID: PMC164218 DOI: 10.1128/cmr.16.3.546-568.2003] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a significant contemporary health problem in the United States and elsewhere. Because it is primarily transmitted via blood, hepatitis C infection presents risks for both nosocomial transmission to patients and occupational spread to health care workers. Recent insights into the pathogenesis, immunopathogenesis, natural history, and treatment of infection caused by this unique flavivirus provide a rationale for the use of new strategies for managing occupational hepatitis C infections when they occur. This article reviews this developing information. Recently published data demonstrate success rates in the treatment of "acute hepatitis C syndrome" that approach 100\%, and although these studies are not directly applicable to all occupational infections, they may provide important clues to optimal management strategies. In addition, the article delineates approaches to the prevention of occupational exposures and also addresses the difficult issue of managing HCV-infected health care providers. The article summarizes currently available data about the nosocomial epidemiology of HCV infection and the magnitude of risk and discusses several alternatives for managing exposure and infection. No evidence supports the use of immediate postexposure prophylaxis with immunoglobulin, immunomodulators, or antiviral agents. Based on the very limited data available, the watchful waiting and preemptive therapy strategies described in detail in this article represent reasonable interim approaches to the complex problem of managing occupational HCV infections, at least until more definitive data are obtained.
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Affiliation(s)
- David K Henderson
- Warren G. Magnuson Clinical Center, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland 20892, USA.
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32
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Abstract
The medical dictionary defines immunization as the "protection of susceptible individuals from communicable diseases by the administration of a living modified agent, a suspension of killed organisms, or an inactivated toxin." This elegant description can be expanded to include twenty-first century approaches to immunization that include recombinant technology, reassortment virus techniques, live vectors, DNA vaccines, and the expansion of the field to encompass noncommunicable diseases such as Alzheimer's disease, autoimmunity, and tumor immunogenetics. Integral to the success of immunization is our knowledge of the immune system's memory of antigens, yet our understanding of this fundamental feature remains limited. On a global scale, communicable diseases remain the number-one cause of morbidity and mortality; hence Jenner's pioneering work with its birth in 1796 still has a challenging and exciting future.
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Affiliation(s)
- Edina H Moylett
- Department of Allergy and Immunology, Texas Children's Hospital, Baylor College of Medicine, 6621 Fannin Street (MC-FC330.01), Houston, TX 77030, USA
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33
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Abstract
The hepatitis C virus (HCV) is a small enveloped RNA virus belonging to the family flaviviridae and genus hepacivirus. The HCV RNA genome is 9,600 nucleotides in length and encodes a single polyprotein that is post-translationally cleaved into 10 polypeptides including t3 structural (C, E1, and E2) and multiple nonstructural proteins ([NS] NS2 to NS5). The NS proteins include enzymes necessary for protein processing (proteases) and viral replication (RNA polymerase). The virus replicates at a high rate in the liver and has marked sequence heterogeneity. There are 6 genotypes and more than 90 subtypes of HCV, the most common in the United States being 1a and 1b (approximately 75%), 2a and 2b (approximately 15%), and 3 (approximately 7%). Acute hepatitis C is marked by appearance of HCV RNA in serum within 1 to 2 weeks of exposure followed by serum alanine aminotransferase (ALT) elevations, and then symptoms and jaundice. Antibody to HCV (anti-HCV) tends to arise late. In acute resolving hepatitis, HCV RNA is cleared and serum ALT levels fall to normal. However, 55% to 85% of patients do not clear virus, but develop chronic hepatitis C. Chronic hepatitis C is often asymptomatic, but is usually associated with persistent or fluctuating elevations in ALT levels. The chronic sequelae of hepatitis C include progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Extra-hepatic manifestations include sicca syndrome, cryoglobulinemia, glomerulonephritis, and porphyria cutanea tarda. Knowledge of the course and outcome of hepatitis C is important in developing approaches to management and therapy.
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Affiliation(s)
- Jay H Hoofnagle
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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34
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Abstract
The hepatitis C virus (HCV) is a small enveloped RNA virus belonging to the family flaviviridae and genus hepacivirus. The HCV RNA genome is 9,600 nucleotides in length and encodes a single polyprotein that is post-translationally cleaved into 10 polypeptides including t3 structural (C, E1, and E2) and multiple nonstructural proteins ([NS] NS2 to NS5). The NS proteins include enzymes necessary for protein processing (proteases) and viral replication (RNA polymerase). The virus replicates at a high rate in the liver and has marked sequence heterogeneity. There are 6 genotypes and more than 90 subtypes of HCV, the most common in the United States being 1a and 1b (approximately 75%), 2a and 2b (approximately 15%), and 3 (approximately 7%). Acute hepatitis C is marked by appearance of HCV RNA in serum within 1 to 2 weeks of exposure followed by serum alanine aminotransferase (ALT) elevations, and then symptoms and jaundice. Antibody to HCV (anti-HCV) tends to arise late. In acute resolving hepatitis, HCV RNA is cleared and serum ALT levels fall to normal. However, 55% to 85% of patients do not clear virus, but develop chronic hepatitis C. Chronic hepatitis C is often asymptomatic, but is usually associated with persistent or fluctuating elevations in ALT levels. The chronic sequelae of hepatitis C include progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Extra-hepatic manifestations include sicca syndrome, cryoglobulinemia, glomerulonephritis, and porphyria cutanea tarda. Knowledge of the course and outcome of hepatitis C is important in developing approaches to management and therapy.
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Affiliation(s)
- Jay H Hoofnagle
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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35
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Quinti I, Pierdominici M, Marziali M, Giovannetti A, Donnanno S, Chapel H, Bjorkander J, Aiuti F. European surveillance of immunoglobulin safety--results of initial survey of 1243 patients with primary immunodeficiencies in 16 countries. Clin Immunol 2002; 104:231-6. [PMID: 12217332 DOI: 10.1006/clim.2002.5239] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
A European multicenter study was conducted to obtain information on the current practices of immunoglobulin administration, the policies in use for the surveillance of the risk of hepatitis C virus (HCV) transmission, and the natural history of HCV infection in patients with hypogammaglobulinemia. Data from 1243 patients with primary immunodeficiencies in 16 countries demonstrated that 90% of patients with antibody deficiencies receive intravenous immunoglobulins in an inpatient setting, and 7% of patients are treated with subcutaneous immunoglobulins, mainly at home. Wide variations have been reported regarding the frequency and the type of tests monitored for the surveillance on the risk of viral hepatitis transmission. Only 60% of patients have been tested at least once for HCV RNA detection. Data from 71 HCV-infected patients demonstrated a rapid progression of HCV infection, with end-stage liver disease, in about 40% of patients. Ten percent of patients spontaneously cleared the virus, and about 30% are asymptomatic. Patients with CVID have a worse prognosis than patients with XLA.
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Affiliation(s)
- Isabella Quinti
- Department of Clinical Immunology, University of Rome La Sapienza, Viale dell'Università 37, 00185, Rome, Italy.
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36
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Abstract
Hepatitis C virus, a recently identified member of the family Flaviviridae, is an important cause of chronic viral hepatitis and cirrhosis. There are similarities in the nature of the immune response to this pathogen with immunity in other flavivirus and hepatotropic virus infections, such as hepatitis B. However, the high rate of viral persistence after primary hepatitis C infection, and the observation that neutralizing antibodies are not protective, would suggest that there are a number of important differences between hepatitis C, other flaviviruses, and hepatitis B. The phenomenon of quasispecies evolution and other viral factors have been proposed to contribute to immune evasion by hepatitis C virus. In the face of established persistent infection, virus-specific cytotoxic T lymphocytes may exert some control over viral replication. However, these same effectors may also be responsible for the progressive liver damage characteristic of chronic hepatitis C infection. The nature of protective immunity, including the role of innate immune responses early after hepatitis C exposure, remains to be defined.
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Affiliation(s)
- A J Freeman
- Viral Hepatitis Research, Gastrointestinal and Liver Unit, The Prince of Wales Hospital, Randwick, New South Wales, Australia.
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37
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Razvi S, Schneider L, Jonas MM, Cunningham-Rundles C. Outcome of intravenous immunoglobulin-transmitted hepatitis C virus infection in primary immunodeficiency. Clin Immunol 2001; 101:284-8. [PMID: 11726220 DOI: 10.1006/clim.2001.5132] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Physicians in the United States who treat patients with primary immunodeficiency were contacted to identify subjects who had been infected with hepatitis C due to exposure to contaminated intravenous immunoglobulin (IVIg) in 1993-1994. From this survey we gathered information on 58 PCR-positive hepatitis C-infected patients; 37 had CVID, 9 had XLA, 5 were IgG subclass deficient, 4 were antibody deficient with normal immunoglobulin levels, 2 had SCID after BMT, and 1 had B cell linker deficiency. Of the 58 subjects, 30 had been treated with IFN-alpha in combination with ribavirin in 5 cases, and 26 other subjects were not treated. Of those who were treated, 11 (37%) resolved the infection and became PCR-negative; of the 26 who were not treated, 5 (19%) have resolved the infection, outcomes not significantly different. Patients 20 years of age or younger had a significantly better outcome compared to those older than age 20 (P = 0.02). Five subjects of the 58 have had a liver transplantation, a sixth has had two transplants, and 10 (17%) of the group have died. This survey demonstrates the heterogeneity of the clinical outcome in subjects with primary immunodeficiency who contracted hepatitis C due to viral contamination of IVIg.
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Affiliation(s)
- S Razvi
- The Department of Medicine, Mount Sinai School of Medicine, New York City, New York 10029, USA
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38
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Affiliation(s)
- G P Spickett
- Regional Department of Immunology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
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39
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Chapel HM, Christie JM, Peach V, Chapman RW. Five-year follow-up of patients with primary antibody deficiencies following an outbreak of acute hepatitis C. Clin Immunol 2001; 99:320-4. [PMID: 11358426 DOI: 10.1006/clim.2001.5036] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
This report is the 5-year follow-up of those 25 UK patients with primary antibody deficiencies infected with hepatitis C virus (HCV), type 1a, from one batch of contaminated anti-HCV-screened intravenous immunoglobulin in 1993-1994. Of these patients, who were reported previously (1, 2), 2 cleared HCV spontaneously, 18 received early interferon-alpha (IFN) treatment for 6 months, and 5 declined treatment or treatment was contraindicated. The clinical course of this cohort was followed prospectively using serial standardized questionnaires. Seven patients (54% of those who had completed therapy) had a sustained response (normal transaminase levels, negative serum HCV RNA) for 5 years posttreatment. Eight patients died: 3 from decompensated cirrhosis, 2 from pneumonia but with evidence of liver failure, and 3 from unrelated causes. One further patient developed decompensated cirrhosis but was successfully transplanted. Seven patients remain chronically infected; only 1 patient is symptomatic but 1 further patient has evidence of progressive fibrosis on liver histology. In conclusion, within 5 years, rapid end-stage HCV liver disease has been seen in 6/25 (24%) patients. Seven patients, (54% of those fully treated) remain well after treatment, making 9/25 (36% of the cohort) clear of virus after 5 years. Those who completed early treatment with IFN had a relatively high sustained response rate compared to previous studies in both immunodeficient and immunocompetent patients.
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Affiliation(s)
- H M Chapel
- Department of Clinical Immunology, John Radcliffe Hospital, Oxford, OX3 9DU, England
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40
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Tillmann HL, Chen DF, Trautwein C, Kliem V, Grundey A, Berning-Haag A, Böker K, Kubicka S, Pastucha L, Stangel W, Manns MP. Low frequency of HLA-DRB1*11 in hepatitis C virus induced end stage liver disease. Gut 2001; 48:714-8. [PMID: 11302974 PMCID: PMC1728277 DOI: 10.1136/gut.48.5.714] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hepatitis C virus (HCV) infection becomes chronic in more than 70% of patients, leading to end stage liver disease in about 20-30% of these patients. Apart from the virus itself, host factors that modulate the immune response are likely to be involved in determining the outcome of HCV infection. Studies on the association of human leucocyte antigens (HLAs) and HCV infection have shown inconsistent results. Selection of patient subgroups may be crucial. However, any association relevant to HCV disease progression will become evident, especially in those patients with end stage liver disease. Therefore, we analysed the phenotype frequencies of HLA antigens in two groups of 69 and 39 patients with HCV induced liver cirrhosis who had received a transplant or were awaiting liver transplantation. The first group was typed serologically and compared with 331 blood and liver donors. The second group, prospectively HLA typed by a polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) procedure for HLA-DRB and DQB alleles, was compared with another 170 PCR-SSO typed and randomly selected blood donors. Decreased frequencies for HLA-DR5 and HLA-DQ3 were found in one group of patients with HCV induced liver cirrhosis compared with the control groups. In the second analysis comparing 39 patients with end stage liver cirrhosis with blood donors, we confirmed the significant decrease in HLA-DRB1*11 and HLA-DQB1*03, which corresponded to serological HLA-DR5 and HLA-DQ3 antigens, respectively. Our results show that the presence of HLA-DRB1*11 and HLA-DQB1*03 alleles is associated with a reduced risk for the development of HCV induced end stage liver disease.
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Affiliation(s)
- H L Tillmann
- Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany
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41
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42
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Hadziyannis SJ, Vassilopoulos D. Complex management issues: management of HCV in the atypical patient. Best Pract Res Clin Gastroenterol 2000; 14:277-91. [PMID: 10890322 DOI: 10.1053/bega.1999.0076] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
Abstract
Some patients with chronic hepatitis C virus (HCV) infection demonstrate atypical features of presentation and clinical course. These features may be due to direct or indirect effects of the underlying HCV infection or may be part of a separate clinical syndrome. Patients that can be categorized as 'atypical' include immunosuppressed individuals (hypogammaglobulinaemic, co-infected with human immunodeficiency virus, recipients of solid organ or haematopoietic cell transplants, those with associated disease requiring chronic immunosuppressive therapy and patients with chronic renal failure on haemodialysis) as well as patients with various extra-hepatic (HCV-associated mixed cryoglobulinaemia, membranoproliferative glomerulonephritis etc) or autoimmune manifestations. Since many of these patients have been excluded from the large trials evaluating the efficacy of interferon-alpha alone or in combination with ribavirin, data regarding management are limited. In this chapter, the available information regarding the treatment of these patients is reviewed and the frequently encountered therapeutic dilemmas discussed. Finally, some reasonable therapeutic approaches are suggested while the need for controlled studies for these groups of patients is emphasized.
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Affiliation(s)
- S J Hadziyannis
- Academic Department of Medicine, Hippokration General Hospital, Athens, Greece
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43
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Lee AY, Polakos NK, Otten GR, Ulmer JB, Houghton M, Paliard X. Quantification of the number of cytotoxic T cells specific for an immunodominant HCV-specific CTL epitope primed by DNA immunization. Vaccine 2000; 18:1962-8. [PMID: 10699347 DOI: 10.1016/s0264-410x(99)00486-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Priming of strong cellular immune responses to hepatitis C (HCV) is thought to be important for eradication of infection. Although productive infection of HCV occurs only reproducibly in humans and chimpanzees, definition of HCV-specific T cell epitopes in mice is necessary to screen efficiently HCV vaccine strategies for their ability to prime cellular immune responses. Out of seven strains of mice screened for immunodominant CTL epitopes against HCV-1a Core, E2, NS5a and NS5b, only one epitope (p214K9) in only one mouse strain was identified. Enumeration of p214K9-specific CD8+ cells by flow cytometry revealed that the number of epitope specific CTL primed by 'naked' DNA immunization was lower than that reported during viral infection. The p214K9 epitope described here, combined with analysis of CTL responses by flow cytometry, should be instrumental in ranking various HCV vaccine strategies for their ability to prime CTL responses.
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MESH Headings
- Animals
- Cell Line
- Cytotoxicity Tests, Immunologic
- Epitopes, T-Lymphocyte/administration & dosage
- Epitopes, T-Lymphocyte/immunology
- Female
- Hepacivirus/immunology
- Hepatitis C/immunology
- Immunodominant Epitopes/administration & dosage
- Immunodominant Epitopes/immunology
- Injections, Intramuscular
- Lymphocyte Count
- Mice
- Mice, Inbred AKR
- Mice, Inbred BALB C
- Mice, Inbred C3H
- Mice, Inbred CBA
- Mice, Inbred DBA
- T-Lymphocytes, Cytotoxic/cytology
- T-Lymphocytes, Cytotoxic/immunology
- Vaccines, DNA/immunology
- Viral Vaccines/immunology
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Affiliation(s)
- A Y Lee
- Chiron Corporation, 4560 Horton Street, Emeryville, CA 94608, USA
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44
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Abstract
Hepatitis C virus (HCV) infection is associated with a wide spectrum of clinical manifestations which may influence the choice of diagnostic assays, especially in haemodialysis patients, the clinical course of infection with possible multiple and sequential episodes of hepatitis in multiple transfused patients, and the severity of liver disease, especially in patients with HBV-HCV co-infection. The consequences of HCV infection in patients with organ graft are not completely understood due to the complexity of the clinical situations and the unavailability of long-term follow-up. Furthermore, current antiviral therapy is not very effective in these populations. Thus, it is especially important to protect patients at risk for HCV infection, using universal precautionary procedures.
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Affiliation(s)
- F Zoulim
- Hôtel Dieu Hospital, and Hepatitis Research Unit INSERM 271, Lyon, France.
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45
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Houghton M. Strategies and prospects for vaccination against the hepatitis C viruses. Curr Top Microbiol Immunol 1999; 242:327-39. [PMID: 10592667 DOI: 10.1007/978-3-642-59605-6_15] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- M Houghton
- Chiron Corporation, Emeryville, CA 94608, USA
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46
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Christie JM, Chapel H, Chapman RW, Rosenberg WM. Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus. Hepatology 1999; 30:1037-44. [PMID: 10498657 DOI: 10.1002/hep.510300403] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
How Hepatitis C Virus (HCV) causes persistent infection is unknown. One hypothesis is that HCV evades the host immune response through mutation in immune epitopes. We have investigated mutations in the HCV genome to see if they cluster within immune epitopes; and we have studied the effect of antibody deficiency on mutation rates. We studied patients with chronic hepatitis C, 3 with antibody deficiency and 3 with normal immunity. Regions of the core and envelope genes of HCV, encoding cytotoxic (CTL), and B cell epitopes were sequenced at 2 time points, 2 years apart. The diversity of quasispecies increased with time. The HCV genetic mutation rate was higher than previously predicted. The cryptic nucleotide mutation rate in core was similar to that observed in envelope, suggesting that the error rate of the HCV RNA polymerase is similar in both regions. In contrast, the coding mutation rate was decreased in core and increased in envelope. No genetic mutation was seen in any of the core CTL epitopes despite detectable cellular responses. All patients had mutations within a previously described envelope CTL epitope but did not exhibit immune responses to either index or mutated peptides. There was no difference in mutation rates in any cellular or humoral epitopes between patients with antibody deficiency and normal immunity. Thus we have found no evidence that mutations were selected by T-lymphocytes or antibodies. These findings implicate alternative virus-host interactions in the selection of HCV mutations.
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Affiliation(s)
- J M Christie
- Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK
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Cooper S, Erickson AL, Adams EJ, Kansopon J, Weiner AJ, Chien DY, Houghton M, Parham P, Walker CM. Analysis of a successful immune response against hepatitis C virus. Immunity 1999; 10:439-49. [PMID: 10229187 DOI: 10.1016/s1074-7613(00)80044-8] [Citation(s) in RCA: 583] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
To investigate the type of immunity responsible for resolution of hepatitis C virus (HCV) infection, we monitored antibody and intrahepatic cytotoxic T lymphocyte (CTL) responses during acute (<20 weeks) infection in chimpanzees. Two animals who terminated infection made strong CTL but poor antibody responses. In both resolvers, CTL targeted at least six viral regions. In contrast, animals developing chronic hepatitis generated weaker acute CTL responses. Extensive analysis of the fine specificity of the CTL in one resolver revealed nine peptide epitopes and restriction by all six MHC class I allotypes. Every specificity shown during acute hepatitis persisted in normal liver tissue more than 1 yr after resolution. These results suggest that CD8+CTL are better correlated with protection against HCV infection than antibodies.
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Affiliation(s)
- S Cooper
- Department of Structural Biology, Stanford University School of Medicine, California 94305-5400, USA.
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