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Al-Tawfiq JA, Spinola SM. Infections caused by Haemophilus ducreyi: one organism, two stories. Clin Microbiol Rev 2024; 37:e0013524. [PMID: 39287406 PMCID: PMC11629627 DOI: 10.1128/cmr.00135-24] [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] [Indexed: 09/19/2024] Open
Abstract
SUMMARYChancroid, a sexually transmitted infection caused by Haemophilus ducreyi, is characterized by painful genital ulcers (GU) and inguinal lymphadenitis. H. ducreyi was recently described as a major cause of non-sexually transmitted cutaneous ulcers (CU) on the lower legs in children in yaws-endemic regions. This review explores the relationship between CU and GU strains of H. ducreyi; their clinical presentation, diagnosis, epidemiology, and treatment; and how findings from a human challenge model relate to GU and CU. We contrast the decline of GU with the persistence of CU caused by H. ducreyi. Factors such as transmission dynamics, control, and elimination efforts are discussed. Syndromic management and targeted treatment of sex workers can eradicate chancroid, while skin colonization by CU strains and environmental factors may necessitate topical treatments or vaccination for CU eradication. Efforts should focus on identifying additional reservoirs of CU strains, improving hygiene, and eliminating asymptomatic colonization to eradicate this painful infection in children.
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Affiliation(s)
- Jaffar A. Al-Tawfiq
- Infectious Disease Unit, Specialty Internal Medicine, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
- Department of Medicine, Division of Infectious Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Division of Infectious Diseases, Johns Hopkins University, Baltimore, Maryland, USA
| | - Stanley M. Spinola
- Department of Medicine, Division of Infectious Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indiana University, Indianapolis, Indiana, USA
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indiana University, Indianapolis, Indiana, USA
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2
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Bourne N, Keith CA, Miller AL, Pyles RB, Cohen G, Milligan GN. Boosting of vaginal HSV-2-specific B and T cell responses by intravaginal therapeutic immunization results in diminished recurrent HSV-2 disease. J Virol 2023; 97:e0066923. [PMID: 37655939 PMCID: PMC10537585 DOI: 10.1128/jvi.00669-23] [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: 05/05/2023] [Accepted: 07/02/2023] [Indexed: 09/02/2023] Open
Abstract
Boosting herpes simplex virus (HSV)-specific immunity in the genital tissues of HSV-positive individuals to increase control of HSV-2 recurrent disease and virus shedding is an important goal of therapeutic immunization and would impact HSV-2 transmission. Experimental therapeutic HSV-2 vaccines delivered by a parenteral route have resulted in decreased recurrent disease in experimental animals. We used a guinea pig model of HSV-2 infection to test if HSV-specific antibody and cell-mediated responses in the vaginal mucosa would be more effectively increased by intravaginal (Ivag) therapeutic immunization compared to parenteral immunization. Therapeutic immunization with HSV glycoproteins and CpG adjuvant increased glycoprotein-specific IgG titers in vaginal secretions and serum to comparable levels in Ivag- and intramuscular (IM)-immunized animals. However, the mean numbers of HSV glycoprotein-specific antibody secreting cells (ASCs) and IFN-γ SCs were greater in Ivag-immunized animals demonstrating superior boosting of immunity in the vaginal mucosa compared to parenteral immunization. Therapeutic Ivag immunization also resulted in a significant decrease in the cumulative mean lesion days compared to IM immunization. There was no difference in the incidence or magnitude of HSV-2 shedding in either therapeutic immunization group compared to control-treated animals. Collectively, these data demonstrated that Ivag therapeutic immunization was superior compared to parenteral immunization to boost HSV-2 antigen-specific ASC and IFN-γ SC responses in the vagina and control recurrent HSV-2 disease. These results suggest that novel antigen delivery methods providing controlled release of optimized antigen/adjuvant combinations in the vaginal mucosa would be an effective approach for therapeutic HSV vaccines. IMPORTANCE HSV-2 replicates in skin cells before it infects sensory nerve cells where it establishes a lifelong but mostly silent infection. HSV-2 occasionally reactivates, producing new virus which is released back at the skin surface and may be transmitted to new individuals. Some HSV-specific immune cells reside at the skin site of the HSV-2 infection that can quickly activate and clear new virus. Immunizing people already infected with HSV-2 to boost their skin-resident immune cells and rapidly control the new HSV-2 infection is logical, but we do not know the best way to administer the vaccine to achieve this goal. In this study, a therapeutic vaccine given intravaginally resulted in significantly better protection against HSV-2 disease than immunization with the same vaccine by a conventional route. Immunization by the intravaginal route resulted in greater stimulation of vaginal-resident, virus-specific cells that produced antibody and produced immune molecules to rapidly clear virus.
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Affiliation(s)
- Nigel Bourne
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA
- Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, Texas, USA
| | - Celeste A. Keith
- Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA
| | - Aaron L. Miller
- Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA
| | - Richard B. Pyles
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA
- Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, Texas, USA
| | - Gary Cohen
- Department of Basic and Translational Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Gregg N. Milligan
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, USA
- Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, Texas, USA
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Dhillon SK, Kura MM. Clinico-epidemiological profile of genital dermatoses in people living with HIV: A shifting paradigm from venereal to nonvenereal dermatoses. Indian J Sex Transm Dis AIDS 2023; 44:11-14. [PMID: 37457512 PMCID: PMC10343133 DOI: 10.4103/ijstd.ijstd_39_22] [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: 03/29/2022] [Revised: 07/13/2022] [Accepted: 10/08/2022] [Indexed: 12/13/2022] Open
Abstract
Context The protean mucocutaneous manifestations of HIV and the resultant opportunistic infections are well documented. Genital dermatoses can be either venereal or nonvenereal in origin. As the presence of HIV infection greatly increases the chances of acquiring another sexually transmitted pathogen, these are often presumed to be venereal in origin. Aims The aims of the study were to record the different morphologies of genital skin lesions in seropositive patients and to classify them as venereal or nonvenereal in origin. Settings and Design This was an observational study undertaken in seropositive patients with genital skin lesions attending the outpatient department of dermatology at a tertiary health-care center. Subjects and Methods One hundred and seventy-seven seropositive patients with genital lesions were enrolled. A detailed history was taken; the genital and dermatological examination was performed. Statistical Analysis Used None. Results Males predominated the study population with the majority (79.1%) falling into the reproductive age group of 15-49 years. Nonvenereal genital dermatoses (59%) outnumbered sexually transmitted infections (STIs) (41%) out of which the most frequently encountered were dermatophytosis, scabies, and intertrigo. Other entities recorded were inflammatory dermatoses, cutaneous adverse drug reactions, and tumors. The most common STIs were herpes genitalis (55.4%) and anogenital warts (32.5%). Conclusion This study showed that nonvenereal genital dermatoses are more common than STIs in people living with HIV. Our findings reiterate the fact that genital lesions should be approached with caution as a presumptive and hasty diagnosis of STI adds greatly to the morbidity of the patient in terms of guilt and shame, and adversely affects the quality of life.
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Affiliation(s)
- Supreet Kaur Dhillon
- Department of Dermatology, Venereology and Leprosy, Grant Government Medical College and Sir JJ Group of Hospitals, Mumbai, Maharashtra, India
| | - Mahendra M. Kura
- Department of Dermatology, Venereology and Leprosy, Grant Government Medical College and Sir JJ Group of Hospitals, Mumbai, Maharashtra, India
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Gupta M, Manek G, Dombrowski K, Maiwall R. Newer developments in viral hepatitis: Looking beyond hepatotropic viruses. World J Meta-Anal 2021; 9:522-542. [DOI: 10.13105/wjma.v9.i6.522] [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: 07/16/2021] [Revised: 09/09/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis in the entirety of its clinical spectrum is vast and most discussion are often restricted to hepatotropic viral infections, including hepatitis virus (A to E). With the advent of more advanced diagnostic techniques, it has now become possible to diagnose patients with non-hepatotropic viral infection in patients with hepatitis. Majority of these viruses belong to the Herpes family, with characteristic feature of latency. With the increase in the rate of liver transplantation globally, especially for the indication of acute hepatitis, it becomes even more relevant to identify non hepatotropic viral infection as the primary hepatic insult. Immunosuppression post-transplant is an established cause of reactivation of a number of viral infections that could then indirectly cause hepatic injury. Antiviral agents may be utilized for treatment of most of these infections, although data supporting their role is derived primarily from case reports. There are no current guidelines to manage patients suspected to have viral hepatitis secondary to non-hepatotropic viral infection, a gap that needs to be addressed. In this review article, the authors analyze the common non hepatotropic viral infections contributing to viral hepatitis, with emphasis on recent advances on diagnosis, management and role of liver transplantation.
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Affiliation(s)
- Manasvi Gupta
- Department of Internal Medicine, University of Connecticut, Farmington, CT 06030, United States
| | - Gaurav Manek
- Department of Pulmonology and Critical Care, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Kaitlyn Dombrowski
- Department of Internal Medicine, University of Connecticut, Farmington, CT 06030, United States
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110070, India
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Shan T, Ye J, Jia J, Wang Z, Jiang Y, Wang Y, Wang Y, Zheng K, Ren Z. Viral UL8 Is Involved in the Antiviral Activity of Oleanolic Acid Against HSV-1 Infection. Front Microbiol 2021; 12:689607. [PMID: 34354687 PMCID: PMC8329587 DOI: 10.3389/fmicb.2021.689607] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 06/29/2021] [Indexed: 11/16/2022] Open
Abstract
Herpes simplex virus type 1 (HSV-1) is highly prevalent in humans and can cause severe diseases, especially in immunocompromised adults and newborns, such as keratitis and herpes simplex encephalitis. At present, the clinical therapeutic drug against HSV-1 infection is acyclovir (ACV), and its extensive usage has led to the emergence of ACV-resistant strains. Therefore, it is urgent to explore novel therapeutic targets and anti-HSV-1 drugs. This study demonstrated that Oleanolic acid, a pentacyclic triterpenoid widely existing in natural product, had strong antiviral activity against both ACV-sensitive and -resistant HSV-1 strains in different cells. Mechanism studies showed that Oleanolic acid exerted its anti-HSV-1 activity in the immediate early stage of infection, which involved the dysregulation of viral UL8, a component of viral helicase-primase complex critical for viral replication. In addition, Oleanolic acid significantly ameliorated the skin lesions in an HSV-1 infection mediated zosteriform model. Together, our study suggested that Oleanolic acid could be a potential candidate for clinical therapy of HSV-1 infection-related diseases.
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Affiliation(s)
- Tianhao Shan
- Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China.,Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China.,Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China.,Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China.,Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, China.,National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Ju Ye
- Key Laboratory of Plant Chemistry in Qinghai-Tibet Plateau, Qinghai University for Nationalities, Xining, China
| | - Jiaoyan Jia
- Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China.,Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China.,Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China.,Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China.,Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, China.,National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Zhaoyang Wang
- Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China.,Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China.,Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China.,Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China.,Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, China.,National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Yuzhou Jiang
- Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China.,Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China.,Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China.,Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China.,Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, China.,National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Yiliang Wang
- Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China.,Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China.,Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China.,Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China.,Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, China.,National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Yifei Wang
- Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China.,Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China.,Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China.,Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China.,Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, China.,National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Kai Zheng
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China
| | - Zhe Ren
- Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China.,Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China.,Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China.,Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China.,Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, China.,National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China
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Harfouche M, Abu-Hijleh FM, James C, Looker KJ, Abu-Raddad LJ. Epidemiology of herpes simplex virus type 2 in sub-Saharan Africa: Systematic review, meta-analyses, and meta-regressions. EClinicalMedicine 2021; 35:100876. [PMID: 34027335 PMCID: PMC8129943 DOI: 10.1016/j.eclinm.2021.100876] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 04/13/2021] [Accepted: 04/14/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Herpes simplex virus type 2 (HSV-2) infection is a prevalent, sexually transmitted infection with a sizable disease burden that is highest in sub-Saharan Africa. This study aimed to characterize HSV-2 epidemiology in this region. METHODS Cochrane and PRISMA guidelines were followed to systematically review, synthesize, and report HSV-2 related findings up to August 23, 2020. Meta-analyses and meta-regressions were conducted. FINDINGS From 218 relevant publications, 451 overall outcome measures and 869 stratified measures were extracted. Pooled incidence rates ranged between 2.4-19.4 per 100 person-years across populations. Pooled seroprevalence was lowest at 37.3% (95% confidence interval (CI): 34.9-39.7%) in general populations and high in female sex workers and HIV-positive individuals at 62.5% (95% CI: 54.8-70.0%) and 71.3% (95% CI: 66.5-75.9%), respectively. In general populations, pooled seroprevalence increased steadily with age. Compared to women, men had a lower seroprevalence with an adjusted risk ratio (ARR) of 0.61 (95% CI: 0.56-0.67). Seroprevalence has decreased in recent decades with an ARR of 0.98 (95% CI: 0.97-0.99) per year. Seroprevalence was highest in Eastern and Southern Africa. Pooled HSV-2 proportion in genital ulcer disease was 50.7% (95% CI: 44.7-56.8%) and in genital herpes it was 97.3% (95% CI: 84.4-100%). INTERPRETATION Seroprevalence is declining by 2% per year, but a third of the population is infected. Age and geography play profound roles in HSV-2 epidemiology. Temporal declines and geographic distribution of HSV-2 seroprevalence mirror that of HIV prevalence, suggesting sexual risk behavior has been declining for three decades. HSV-2 is the etiological cause of half of genital ulcer disease and nearly all genital herpes cases with limited role for HSV-1. FUNDING This work was supported by pilot funding from the Biomedical Research Program at Weill Cornell Medicine in Qatar and by the Qatar National Research Fund [NPRP 9-040-3-008].
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Affiliation(s)
- Manale Harfouche
- Infectious Disease Epidemiology Group, Weill Cornell Medicine-Qatar, Cornell University, Qatar Foundation - Education City, Doha, Qatar
- World Health Organization Collaborating Centre for Disease Epidemiology Analytics on HIV/AIDS, Sexually Transmitted Infections, and Viral Hepatitis, Weill Cornell Medicine–Qatar, Cornell University, Qatar Foundation – Education City, Doha, Qatar
| | - Farah M. Abu-Hijleh
- Department of Public Health, College of Health Sciences, Academic Quality Affairs Office, QU Health, Qatar University, Doha, Qatar
| | - Charlotte James
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Katharine J. Looker
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Laith J. Abu-Raddad
- Infectious Disease Epidemiology Group, Weill Cornell Medicine-Qatar, Cornell University, Qatar Foundation - Education City, Doha, Qatar
- World Health Organization Collaborating Centre for Disease Epidemiology Analytics on HIV/AIDS, Sexually Transmitted Infections, and Viral Hepatitis, Weill Cornell Medicine–Qatar, Cornell University, Qatar Foundation – Education City, Doha, Qatar
- Department of Population Health Sciences, Weill Cornell Medicine, Cornell University, New York, NY, United States
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Kardani K, Basimi P, Fekri M, Bolhassani A. Antiviral therapy for the sexually transmitted viruses: recent updates on vaccine development. Expert Rev Clin Pharmacol 2020; 13:1001-1046. [PMID: 32838584 DOI: 10.1080/17512433.2020.1814743] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The sexually transmitted infections (STIs) caused by viruses including human T cell leukemia virus type-1 (HTLV-1), human immunodeficiency virus-1 (HIV-1), human simplex virus-2 (HSV-2), hepatitis C virus (HCV), hepatitis B virus (HBV), and human papillomavirus (HPV) are major public health issues. These infections can cause cancer or result in long-term health problems. Due to high prevalence of STIs, a safe and effective vaccine is required to overcome these fatal viruses. AREAS COVERED This review includes a comprehensive overview of the literatures relevant to vaccine development against the sexually transmitted viruses (STVs) using PubMed and Sciencedirect electronic search engines. Herein, we discuss the efforts directed toward development of effective vaccines using different laboratory animal models including mice, guinea pig or non-human primates in preclinical trials, and human in clinical trials with different phases. EXPERT OPINION There is no effective FDA approved vaccine against the sexually transmitted viruses (STVs) except for HBV and HPV as prophylactic vaccines. Many attempts are underway to develop vaccines against these viruses. There are several approaches for improving prophylactic or therapeutic vaccines such as heterologous prime/boost immunization, delivery system, administration route, adjuvants, etc. In this line, further studies can be helpful for understanding the immunobiology of STVs in human. Moreover, development of more relevant animal models is a worthy goal to induce effective immune responses in humans.
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Affiliation(s)
- Kimia Kardani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
| | - Parya Basimi
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
| | - Mehrshad Fekri
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
| | - Azam Bolhassani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
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Ayoub HH, Chemaitelly H, Abu-Raddad LJ. Epidemiological Impact of Novel Preventive and Therapeutic HSV-2 Vaccination in the United States: Mathematical Modeling Analyses. Vaccines (Basel) 2020; 8:E366. [PMID: 32650385 PMCID: PMC7564812 DOI: 10.3390/vaccines8030366] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 06/23/2020] [Accepted: 06/25/2020] [Indexed: 12/30/2022] Open
Abstract
This study aims to inform herpes simplex virus type 2 (HSV-2) vaccine development, licensure, and implementation by delineating the population-level impact of vaccination. Mathematical models were constructed to describe the transmission dynamics in presence of prophylactic or therapeutic vaccines assuming 50% efficacy, with application to the United States. Catch-up prophylactic vaccination will reduce, by 2050, annual number of new infections by 58%, incidence rate by 60%, seroprevalence by 21%, and avert yearly as much as 350,000 infections. Number of vaccinations needed to avert one infection was only 50 by 2050, 34 by prioritizing those aged 15-19 years, 4 by prioritizing the highest sexual risk group, 43 by prioritizing women, and 47 by prioritizing men. Therapeutic vaccination of infected adults with symptomatic disease will reduce, by 2050, annual number of new infections by 12%, incidence rate by 13%, seroprevalence by 4%, and avert yearly as much as 76,000 infections. Number of vaccinations needed to avert one infection was eight by 2050, two by prioritizing those aged 15-19 years, three by prioritizing the highest sexual risk group, seven by prioritizing men, and ten by prioritizing women. HSV-2 vaccination offers an impactful and cost-effective intervention to prevent genital herpes medical and psychosexual disease burden.
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Affiliation(s)
- Houssein H. Ayoub
- Department of Mathematics, Statistics, and Physics, Qatar University, Doha 2713, Qatar;
| | - Hiam Chemaitelly
- Infectious Diseases Epidemiology Group, Weill Cornell Medicine–Qatar, Cornell University, Qatar Foundation–Education City, Doha 24144, Qatar;
- World Health Organization Collaborating Centre for Disease Epidemiology Analytics on HIV/AIDS, Sexually Transmitted Infections, and Viral Hepatitis, Weill Cornell Medicine–Qatar, Cornell University, Qatar Foundation–Education City, Doha 24144, Qatar
| | - Laith J. Abu-Raddad
- Infectious Diseases Epidemiology Group, Weill Cornell Medicine–Qatar, Cornell University, Qatar Foundation–Education City, Doha 24144, Qatar;
- World Health Organization Collaborating Centre for Disease Epidemiology Analytics on HIV/AIDS, Sexually Transmitted Infections, and Viral Hepatitis, Weill Cornell Medicine–Qatar, Cornell University, Qatar Foundation–Education City, Doha 24144, Qatar
- Department of Healthcare Policy and Research, Weill Cornell Medicine, Cornell University, New York City, NY 10065, USA
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Álvarez DM, Castillo E, Duarte LF, Arriagada J, Corrales N, Farías MA, Henríquez A, Agurto-Muñoz C, González PA. Current Antivirals and Novel Botanical Molecules Interfering With Herpes Simplex Virus Infection. Front Microbiol 2020; 11:139. [PMID: 32117158 PMCID: PMC7026011 DOI: 10.3389/fmicb.2020.00139] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 01/21/2020] [Indexed: 12/31/2022] Open
Abstract
Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are highly prevalent within the human population and are characterized by lifelong infections and sporadic recurrences due to latent neuron infection. Upon reactivations, HSVs may manifest either, symptomatically or asymptomatically and be shed onto others through mucosae body fluids. Although, HSVs can produce severe disease in humans, such as life-threatening encephalitis and blindness, the most common symptoms are skin and mucosal lesions in the oro-facial and the genital areas. Nucleoside analogs with antiviral activity can prevent severe HSV infection, yet they are not very effective for treating skin manifestations produced by these viruses, as they only reduce in a few days at most the duration of lesions. Additionally, HSV variants that are resistant to these antivirals may arise, especially in immunosuppressed individuals. Thus, new antivirals that can reduce the severity and duration of these cutaneous manifestations would certainly be welcome. Here, we review currently available anti-herpetic therapies, novel molecules being assessed in clinical trials and new botanical compounds reported in the last 20 years with antiviral activities against HSVs that might represent future treatments against these viruses.
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Affiliation(s)
- Diana M. Álvarez
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Estefanía Castillo
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Luisa F. Duarte
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - José Arriagada
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Nicolás Corrales
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Mónica A. Farías
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Adolfo Henríquez
- Centro de Biotecnología, Universidad de Concepción, Concepción, Chile
| | - Cristian Agurto-Muñoz
- Centro de Biotecnología, Universidad de Concepción, Concepción, Chile
- Departamento de Ciencia y Tecnología de Alimentos, Facultad de Farmacia, Universidad de Concepción, Concepción, Chile
| | - Pablo A. González
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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Gaeta C, Scholand S, Blakey B, Pescatore R. A Young Patient with Painful Penile Lesions. Cureus 2019; 11:e6397. [PMID: 31886100 PMCID: PMC6918799 DOI: 10.7759/cureus.6397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Chancroid is a rare infection in the United States and many other developed countries. Infrequently identified as a cause of genital ulcer disease, chancroid’s atypical presentation has only been reported in approximately 20 cases annually in the United States since 2011. Infection with the causative organism, Haemophilus ducreyi, leads to an erythematous papule that rapidly evolves into a pustule. Infected individuals commonly have more than one ulcer about 2 cm in diameter that is typically noted as painful. The base of the ulcer is usually covered with a gray or yellow purulent exudate and bleeds when scraped. Despite a heavy focus in preclinical medical education, the notably rare chance to see and diagnose chancroid in clinical practice adds to the complicated profile of this infection’s identification and subsequent treatment. Such lack of familiarity contributes to reports of accuracy of clinical diagnosis ranging from 30% to 80%.
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Affiliation(s)
- Christopher Gaeta
- Emergency Medicine, Children's Hospital of Philadelphia, Philadelphia, USA
| | - Stephen Scholand
- Internal Medicine: Infectious Diseases, University of Arizona, Tuscon, USA
| | - Brandon Blakey
- Emergency Medicine, Crozer Keystone Health System, Chester, USA
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Increased Frequency of Virus Shedding by Herpes Simplex Virus 2-Infected Guinea Pigs in the Absence of CD4 + T Lymphocytes. J Virol 2019; 93:JVI.01721-18. [PMID: 30463981 DOI: 10.1128/jvi.01721-18] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 11/16/2018] [Indexed: 01/29/2023] Open
Abstract
Reactivation of herpes simplex virus 2 (HSV-2) results in infection of epithelial cells at the neuro-epithelial junction and shedding of virus at the epithelial surface. Virus shedding can occur in either the presence or absence of clinical disease and is usually of short duration, although the shedding frequency varies among individuals. The basis for host control of virus shedding is not well understood, although adaptive immune mechanisms are thought to play a central role. To determine the importance of CD4+ T cells in control of HSV-2 shedding, this subset of immune cells was depleted from HSV-2-infected guinea pigs by injection of an anti-CD4 monoclonal antibody (MAb). Guinea pigs were treated with the depleting MAb after establishment of a latent infection, and vaginal swabs were taken daily to monitor shedding by quantitative PCR. The cumulative number of HSV-2 shedding days and the mean number of days virus was shed were significantly increased in CD4-depleted compared to control-treated animals. However, there was no difference in the incidence of recurrent disease between the two treatment groups. Serum antibody levels and the number of HSV-specific antibody-secreting cells in secondary lymphoid tissues were unaffected by depletion of CD4+ T cells; however, the frequency of functional HSV-specific, CD8+ gamma interferon-secreting cells was significantly decreased. Together, these results demonstrate an important role for CD4+ T lymphocytes in control of virus shedding that may be mediated in part by maintenance of HSV-specific CD8+ T cell populations. These results have important implications for development of therapeutic vaccines designed to control HSV-2 shedding.IMPORTANCE Sexual transmission of HSV-2 results from viral shedding following reactivation from latency. The immune cell populations and mechanisms that control HSV-2 shedding are not well understood. This study examined the role of CD4+ T cells in control of virus shedding using a guinea pig model of genital HSV-2 infection that recapitulates the shedding of virus experienced by humans. We found that the frequency of virus-shedding episodes, but not the incidence of clinical disease, was increased by depletion of CD4+ T cells. The HSV-specific antibody response was not diminished, but frequency of functional HSV-reactive CD8+ T cells was significantly diminished by CD4 depletion. These results confirm the role of cell-mediated immunity and highlight the importance of CD4+ T cells in controlling HSV shedding, suggesting that therapeutic vaccines designed to reduce transmission by controlling HSV shedding should include specific enhancement of HSV-specific CD4+ T cell responses.
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12
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Bernstein DI, Pullum DA, Cardin RD, Bravo FJ, Dixon DA, Kousoulas KG. The HSV-1 live attenuated VC2 vaccine provides protection against HSV-2 genital infection in the guinea pig model of genital herpes. Vaccine 2019; 37:61-68. [DOI: 10.1016/j.vaccine.2018.11.042] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 11/09/2018] [Accepted: 11/14/2018] [Indexed: 12/12/2022]
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Agyemang E, Magaret AS, Selke S, Johnston C, Corey L, Wald A. Herpes Simplex Virus Shedding Rate: Surrogate Outcome for Genital Herpes Recurrence Frequency and Lesion Rates, and Phase 2 Clinical Trials End Point for Evaluating Efficacy of Antivirals. J Infect Dis 2018; 218:1691-1699. [PMID: 30020484 PMCID: PMC6195656 DOI: 10.1093/infdis/jiy372] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/12/2018] [Indexed: 01/09/2023] Open
Abstract
Background We tested whether genital herpes simplex virus (HSV) shedding is an appropriate surrogate outcome for the clinical outcome of genital herpes lesions in studies of HSV-2 antiviral interventions. Methods We analyzed prospective data from natural history studies and clinical trials of antiviral agents for HSV-2 in which HSV-2-seropositive participants provided self-collected anogenital swab specimens daily over ≥25 days for HSV DNA quantitation by polymerase chain reaction (PCR). Genital recurrences were self-reported. Results Among 674 participants, genital HSV shedding was detected on 17% of days, and genital lesions were reported on 10% of days. Within the same session, HSV shedding rates were strongly correlated with lesion rates (ρ = 0.61, P < .0001). The relative reduction in the recurrence rate was 72% (P = .041) for recipients of the antiviral agent pritelivir as compared to recipients of placebo, but it decreased to 21% (P = .75) after adjustment for HSV shedding rate. When evaluating valacyclovir and acyclovir, adjustment for the HSV shedding rate also led to a reduced association of these antivirals with the recurrence rate. Overall, 40%-82% of the antiviral effect on recurrences was explained by its effect on HSV shedding. Conclusion HSV genital shedding measured by PCR analysis in swab specimens self-collected daily is an appropriate surrogate outcome for genital herpes lesions because it is in the causal pathway to recurrences.
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Affiliation(s)
- Elfriede Agyemang
- Department of Medicine, University of Washington, Seattle, Washington
| | - Amalia S Magaret
- Department of Laboratory Medicine, University of Washington, Seattle, Washington
- Department of Biostatistics, University of Washington, Seattle, Washington
- Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Stacy Selke
- Department of Laboratory Medicine, University of Washington, Seattle, Washington
| | - Christine Johnston
- Department of Medicine, University of Washington, Seattle, Washington
- Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Larry Corey
- Department of Medicine, University of Washington, Seattle, Washington
- Department of Laboratory Medicine, University of Washington, Seattle, Washington
- Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Anna Wald
- Department of Medicine, University of Washington, Seattle, Washington
- Department of Laboratory Medicine, University of Washington, Seattle, Washington
- Department of Epidemiology, University of Washington, Seattle, Washington
- Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
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14
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Prophylactic herpes simplex virus type 2 vaccine adjuvanted with a universal CD4 T cell helper peptide induces long-term protective immunity against lethal challenge in mice. Int Immunopharmacol 2018; 61:100-108. [PMID: 29857239 DOI: 10.1016/j.intimp.2018.05.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 05/12/2018] [Accepted: 05/23/2018] [Indexed: 12/16/2022]
Abstract
Induction of robust and long-term immune responses at the portal of entry remains a big challenge for HSV-2 vaccine development. The adoption of a CD4 T cell helper peptide in the vaccine is thought to be beneficial for the enhancement of immune responses, however, its effect on HSV-2 vaccines has not yet been studied. In this study, we designed a DNA vaccine (gD-TpD) simultaneously expressing HSV-2 gD ectodomain and a universal CD4 T cell helper peptide (TpD), and tested its efficacy on a murine model. Mice were immunized 3 times with gD-TpD or control DNA formulations, and then were rested until Day 150 when they were vaginally challenged with lethal doses of HSV-2. Our data showed that gD-TpD significantly increased gD-specific IgG and IgA in both sera and vaginal washes. Furthermore, the increased antibody responses showed enhanced neutralization activity in vitro. In addition, gD-TpD induced balanced Th1/2 cellular responses and CD8+ T cell-dependent CTL activity. Although immune responses dropped over time after the final immunization, robust and rapid antibody and T cell responses were induced upon virus challenge in gD-TpD group. Moreover, gD-TpD provided full protection against lethal viral challenge in immunized mice. Together, our findings indicate that the inclusion of the CD4 T cell helper peptide TpD in HSV-2 gD subunit vaccine could induce long-term protective immunity, providing information for a rational design of vaccines against HSV-2 or even other viruses.
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15
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Zorzi A, Cordioli M, Gios L, Del Bravo P, Toskin I, Peeling RW, Blondeel K, Cornaglia G, Kiarie J, Ballard R, Mirandola M. Field evaluation of two point-of-care tests for syphilis among men who have sex with men, Verona, Italy. Sex Transm Infect 2018; 93:S51-S58. [PMID: 29223963 DOI: 10.1136/sextrans-2016-053065] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 05/30/2017] [Accepted: 06/10/2017] [Indexed: 01/13/2023] Open
Abstract
OBJECTIVES The incidence of HIV and syphilis among men who have sex with men (MSM) in Europe has recently increased. Rapid point-of-care tests (POCTs) for syphilis can improve access to screening. The purpose of this study was to evaluate the performance of two syphilis POCTs compared with laboratory tests among MSM. METHODS The study was undertaken in Verona, Italy. Asymptomatic MSM, potentially exposed to syphilis, were enrolled prospectively. The POCTs evaluated were SD Bioline Syphilis 3.0 and Chembio DPP Syphilis Screen & Confirm Assay on both serum and fingerprick blood. The results of the POCTs were read by the naked eye by two independent readers and their concordance assessed. RESULTS A total of 289 MSM were enrolled in the study. Based on laboratory tests, 35 MSM (12.1%) were TPPA-positive alone and 16 (5.5%) were both Treponema pallidum particle agglutination test (TPPA) and rapid plasma reagin (RPR)-positive. The specificities of both POCTs were above 99% on both serum and fingerstick blood specimens, while sensitivities varied considerably. The sensitivity of the SD Bioline test was lower on fingerprick blood (51.4% and 54.3%, readers 1 and 2, respectively) compared with that on serum (80.0% and 82.9%). In contrast, the Chembio test exhibited similar sensitivity values for serum and fingerprick samples (57.7% and 64.0% on serum vs 65.4% and 69.2% on fingerprick for the treponemal component; 63.6% on both samples by both readers for the non-treponemal component). The positive predictive value ranged between 100% and 93.9% for the treponemal component of both syphilis POCTs, but was lower (76.3%-100%)%) for the non-treponemal component of the Chembio POCT. The negative predictive value surpassed 90% for both tests on both samples. The agreement between readers was very high (>99%). CONCLUSION The diagnostic performance of the syphilis POCTs was lower than expected; however, considering the prevalence of syphilis among MSM, POCTs should be recommended to improve syphilis detection among MSM.
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Affiliation(s)
- Antonella Zorzi
- Virology and Microbiology Unit, Department of Pathology and Diagnostics, Verona University Hospital, Verona, Italy
| | - Maddalena Cordioli
- Infectious Diseases Section, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Lorenzo Gios
- Regional Coordination Centre for European Project Management, Verona University Hospital, Verona, Italy
| | - Paola Del Bravo
- Infectious Diseases and Tropical Medicine Unit, Department of General Medicine, Verona University Hospital, Verona, Italy
| | - Igor Toskin
- Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland
| | - Rosanna W Peeling
- International Diagnostics Centre, Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK
| | - Karel Blondeel
- Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland.,Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Giuseppe Cornaglia
- Virology and Microbiology Unit, Department of Pathology and Diagnostics, Verona University Hospital, Verona, Italy
| | - James Kiarie
- Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland
| | - Ronald Ballard
- Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland
| | - Massimo Mirandola
- Infectious Diseases Section, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.,Regional Coordination Centre for European Project Management, Verona University Hospital, Verona, Italy
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16
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Johnston C, Magaret A, Roychoudhury P, Greninger AL, Cheng A, Diem K, Fitzgibbon MP, Huang ML, Selke S, Lingappa JR, Celum C, Jerome KR, Wald A, Koelle DM. Highly conserved intragenic HSV-2 sequences: Results from next-generation sequencing of HSV-2 U L and U S regions from genital swabs collected from 3 continents. Virology 2017; 510:90-98. [PMID: 28711653 PMCID: PMC5565707 DOI: 10.1016/j.virol.2017.06.031] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 06/24/2017] [Accepted: 06/27/2017] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Understanding the variability in circulating herpes simplex virus type 2 (HSV-2) genomic sequences is critical to the development of HSV-2 vaccines. METHODS Genital lesion swabs containing ≥ 107log10 copies HSV DNA collected from Africa, the USA, and South America underwent next-generation sequencing, followed by K-mer based filtering and de novo genomic assembly. Sites of heterogeneity within coding regions in unique long and unique short (UL_US) regions were identified. Phylogenetic trees were created using maximum likelihood reconstruction. RESULTS Among 46 samples from 38 persons, 1468 intragenic base-pair substitutions were identified. The maximum nucleotide distance between strains for concatenated UL_US segments was 0.4%. Phylogeny did not reveal geographic clustering. The most variable proteins had non-synonymous mutations in < 3% of amino acids. CONCLUSIONS Unenriched HSV-2 DNA can undergo next-generation sequencing to identify intragenic variability. The use of clinical swabs for sequencing expands the information that can be gathered directly from these specimens.
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Affiliation(s)
- Christine Johnston
- Department of Medicine, University of Washington, USA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, USA.
| | - Amalia Magaret
- Department of Laboratory Medicine, University of Washington, USA; Department of Biostatistics, University of Washington, USA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, USA
| | | | | | - Anqi Cheng
- Department of Biostatistics, University of Washington, USA
| | - Kurt Diem
- Department of Laboratory Medicine, University of Washington, USA
| | - Matthew P Fitzgibbon
- Genomics and Bioinformatics Resource, Fred Hutchinson Cancer Research Center, USA
| | - Meei-Li Huang
- Department of Laboratory Medicine, University of Washington, USA
| | - Stacy Selke
- Department of Laboratory Medicine, University of Washington, USA
| | - Jairam R Lingappa
- Department of Medicine, University of Washington, USA; Department of Global Health, University of Washington, USA; Department of Pediatrics, University of Washington, USA
| | - Connie Celum
- Department of Medicine, University of Washington, USA; Department of Epidemiology, University of Washington, USA; Department of Global Health, University of Washington, USA
| | - Keith R Jerome
- Department of Laboratory Medicine, University of Washington, USA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, USA
| | - Anna Wald
- Department of Medicine, University of Washington, USA; Department of Laboratory Medicine, University of Washington, USA; Department of Epidemiology, University of Washington, USA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, USA
| | - David M Koelle
- Department of Medicine, University of Washington, USA; Department of Laboratory Medicine, University of Washington, USA; Department of Global Health, University of Washington, USA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, USA; Benaroya Research Institute, Seattle, WA, USA
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Abstract
Syphilis is a chronic bacterial infection caused by Treponema pallidum that is endemic in low-income countries and and occurs at lower rates in middle-income and high-income countries. The disease is of both individual and public health importance and, in addition to its direct morbidity, increases risk of HIV infection and can cause lifelong morbidity in children born to infected mothers. Without treatment the disease can progress over years through a series of clinical stages and lead to irreversible neurological or cardiovascular complications. Although syphilis is an ancient disease and the principles of recommended management have been established for decades, diagnosis and management are often challenging because of its varied manifestations and difficulty in interpretation of serological tests used to confirm diagnosis and evaluate response to therapy. In North America and western Europe, incidence of syphilis has increased dramatically in the past decade among men who have sex with men, particularly those with coexistent HIV infection. Only one drug, penicillin, is recommended for syphilis treatment and response to therapy is assessed based on changes over months in serological test titres. Treatment for patients who cannot receive penicillin and management of patients who do not serologically respond to treatment are common clinical problems.
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Affiliation(s)
- Edward W Hook
- University of Alabama at Birmingham, Birmingham, AL, USA.
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18
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Johnston C, Wald A. Genital Herpes. Infect Dis (Lond) 2017. [DOI: 10.1016/b978-0-7020-6285-8.00062-9] [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: 10/21/2022] Open
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19
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What is the probable cause of this genital ulcer? JAAPA 2016; 28:63-4. [PMID: 25522031 DOI: 10.1097/01.jaa.0000458871.39548.82] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Van Der Pol B. Type-specific detection of herpes simplex virus type 1 and type 2 using the cobas® HSV 1 and 2 test on the cobas® 4800 platform. Expert Rev Mol Diagn 2016; 16:1145-1154. [PMID: 27687862 DOI: 10.1080/14737159.2016.1243473] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION HSV-1 and HSV-2 are among the most common causes of sexually transmitted infections (stis) globally. these infections are strongly associated with increased risk of hiv acquisition and rare, but devastating, neonatal disease. available treatment options can reduce HSV transmission and improve quality of life. accurate diagnosis early in disease can improve patient management. Areas covered: This paper describes the clinical manifestations of HSV infection often used for clinical diagnostic purposes. The paper then describes the evolution of laboratory diagnostic assays. Serology, culture and molecular diagnostics are described since all are currently in use. The features and performance characteristics of the cobas 4800 HSV1 and HSV2 Test (cobas HSV) on the cobas 4800® system (cobas 4800) are described in detail. Expert commentary: Diagnosis of HSV has historically been unreliable or technically difficult, but the availability of molecular assays such as the cobas HSV test for detection and typing of herpes can improve our ability to correctly manage this disease. Utilization of tools such as the cobas HSV assay may help shorten the time to accurate diagnosis and treatment thus potentially reducing the risk of transmission and the global burden of HSV.
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Affiliation(s)
- Barbara Van Der Pol
- a Department of Medicine , University of Alabama at Birmingham School of Medicine , Birmingham , AL , USA
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21
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Shakya G, Singh DR, Ojha HC, Ojha CR, Mishra SK, Malla K, Chaudhary P, Regmi K. Evaluation of SD Bioline HIV/syphilis Duo rapid test kits in Nepal. BMC Infect Dis 2016; 16:450. [PMID: 27566067 PMCID: PMC5002177 DOI: 10.1186/s12879-016-1694-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 07/05/2016] [Indexed: 11/20/2022] Open
Abstract
Background Accurate and prompt diagnosis of HIV and syphilis simultaneously has reinforcing effect on their control program because of their prevalent co-infection. Availability of a simple user-friendly two-pronged and affordable detection tools brings down the cost of health care. They are important in the antenatal clinics, with added opportunity for intervention and prevention of mother to child transmission. In cooperation with rapid test kit manufacturers, SD Bioline, NPHL and NCASC, an evaluation of commercially available HIV/syphilis Duo rapid test kit (SD Bioline) to assess its performance and operational characteristics was done in the present study. Method A prospective laboratory-based cross sectional study was conducted at a large Women’s Hospital. Ten thousand pregnant women, visiting the Hospital for antenatal care or for delivery, were enrolled in study. Tests were performed by the SD Bioline HIV/Syphilis Duo kit as well as national algorithm for HIV and syphilis diagnosis which were considered gold standard. Sensitivity, Specificity, positive predictive value and negative predictive value along with kappa coefficient were calculated for the kit under evaluation. Result The sensitivity, specificity, Negative predictive value and Positive predictive value of the kit for HIV diagnosis were 100 % (95 % CI 83.18–100 %, 99.96–100 %, 83.18–100 %, and 99.96–100 %, respectively). Kappa value was found to be 1.0. Out of total cases, results of 9985 (99.85 %) cases were concordant with National algorithm for syphilis diagnosis. Thirteen (0.13 %) cases were found false positive while two were false negative. The sensitivity of the kit for syphilis diagnosis was found to be 95.45 % (95 % CI 84.86–98.74 %) and specificity was 99.87 % (95 % CI; 99.78–99.92 %). Positive predictive value was 76.36 % (95 % CI; 63.65–85.63 %) and Negative predictive value was 99.89 % (95 % CI; 99.39–99.99 %). Kappa value was found to be 0.85. Conclusion The performance characteristics of SD Bioline HIV/Syphilis duo kit were found almost concordant with the kits being used for HIV and Syphilis diagnosis separately. Its implementation in antenatal clinics/VCTs could be an added opportunity for simultaneous diagnosis of HIV and syphilis.
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Affiliation(s)
- Geeta Shakya
- National Public Health Laboratory, Teku, Kathmandu, Nepal.
| | | | | | - Chet Raj Ojha
- National Public Health Laboratory, Teku, Kathmandu, Nepal
| | | | | | | | - Kiran Regmi
- Family Health Division, Teku, Kathmandu, Nepal
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22
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Current Concepts for Genital Herpes Simplex Virus Infection: Diagnostics and Pathogenesis of Genital Tract Shedding. Clin Microbiol Rev 2016; 29:149-61. [PMID: 26561565 DOI: 10.1128/cmr.00043-15] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Herpes simplex virus 2 (HSV-2) is a DNA virus that is efficiently transmitted through intimate genital tract contact and causes persistent infection that cannot be eliminated. HSV-2 may cause frequent, symptomatic self-limited genital ulcers, but in most persons infection is subclinical. However, recent studies have demonstrated that the virus is frequently shed from genital surfaces even in the absence of signs or symptoms of clinical disease and that the virus can be transmitted during these periods of shedding. Furthermore, HSV-2 shedding is detected throughout the genital tract and may be associated with genital tract inflammation, which likely contributes to increased risk of HIV acquisition. This review focuses on HSV diagnostics, as well as what we have learned about the importance of frequent genital HSV shedding for (i) HSV transmission and (ii) genital tract inflammation, as well as (iii) the impact of HSV-2 infection on HIV acquisition and transmission. We conclude with discussion of future areas of research to push the field forward.
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Johnston C, Gottlieb SL, Wald A. Status of vaccine research and development of vaccines for herpes simplex virus. Vaccine 2016; 34:2948-2952. [PMID: 26973067 DOI: 10.1016/j.vaccine.2015.12.076] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 12/23/2015] [Indexed: 11/27/2022]
Abstract
Herpes simplex virus type-1 (HSV-1) and -2 (HSV-2) are highly prevalent global pathogens which commonly cause recurrent oral and genital ulcerations. Less common but more serious complications include meningitis, encephalitis, neonatal infection, and keratitis. HSV-2 infection is a significant driver of the HIV epidemic, increasing the risk of HIV acquisition 3 fold. As current control strategies for genital HSV-2 infection, including antiviral therapy and condom use, are only partially effective, vaccines will be required to reduce infection. Both preventive and therapeutic vaccines for HSV-2 are being pursued and are in various stages of development. We will provide an overview of efforts to develop HSV-2 vaccines, including a discussion of the clinical need for an HSV vaccine, and status of research and development with an emphasis on recent insights from trials of vaccine candidates in clinical testing. In addition, we will touch upon aspects of HSV vaccine development relevant to low and middle income countries.
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Affiliation(s)
- Christine Johnston
- Department of Medicine, Seattle, WA, USA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
| | - Sami L Gottlieb
- Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland
| | - Anna Wald
- Department of Medicine, Seattle, WA, USA; Laboratory Medicine, University of Washington, Seattle, WA, USA; Seattle, WA, USA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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Diagnostic Approaches to Genitourinary Tract Infections. Mol Microbiol 2016. [DOI: 10.1128/9781555819071.ch28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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25
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Comparison of Diagnostic Accuracy of PCR Targeting the 47-Kilodalton Protein Membrane Gene of Treponema pallidum and PCR Targeting the DNA Polymerase I Gene: Systematic Review and Meta-analysis. J Clin Microbiol 2015; 53:3522-9. [PMID: 26311859 DOI: 10.1128/jcm.01619-15] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 08/20/2015] [Indexed: 12/23/2022] Open
Abstract
Treponema pallidum PCR (Tp-PCR) testing now is recommended as a valid tool for the diagnosis of primary or secondary syphilis. The objectives were to systematically review and determine the optimal specific target gene to be used for Tp-PCR. Comparisons of the performance of the two main targets are tpp47 and polA genes were done using meta-analysis. Three electronic bibliographic databases, representing abstract books from five conferences specialized in infectious diseases from January 1990 to March 2015, were searched. Search keywords included ("syphilis" OR "Treponema pallidum" OR "neurosyphilis") AND ("PCR" OR "PCR" OR "molecular amplification"). We included diagnostic studies assessing the performance of Tp-PCR targeting tpp47 (tpp47-Tp-PCR) or the polA gene (polA-Tp-PCR) in ulcers from early syphilis. All studies were assessed against quality criteria using the QUADAS-2 tool. Of 37 studies identified, 62.2% were judged at low risk of bias or applicability. Most used the U.S. Centers for Disease Control and Prevention (CDC) case definitions for primary or secondary (early) syphilis (89.2%; n = 33); 15 (40.5%) used darkfield microscopy (DFM). We did not find differences in sensitivity and specificity between the two Tp-PCR methods in the subgroup of studies using adequate reference tests. Among studies using DFM as the reference test, sensitivities were 79.8% (95% confidence intervals [CI], 72.7 to 85.4%) and 71.4% (46.0 to 88.0%) for tpp47-Tp-PCR and polA-Tp-PCR (P = 0.217), respectively; respective specificities were 95.3% (93.5 to 96.6%) and 93.7% (91.8 to 95.2%) (P = 0.304). Our findings suggest that the two Tp-PCR methods have similar accuracy and could be used interchangeably.
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McDaniel J, Giovannelli M, Happ MB. Exemplars of complex assessment and care for hospitalized older adults: genital herpes infection. Geriatr Nurs 2015; 35:233-5. [PMID: 24942524 DOI: 10.1016/j.gerinurse.2014.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Jodi McDaniel
- The Ohio State University College of Nursing, Center of Excellence in Critical and Complex Care, 378 Newton Hall, 1585 Neil Ave., Columbus, OH 43210, USA
| | | | - Mary Beth Happ
- The Ohio State University College of Nursing, Center of Excellence in Critical and Complex Care, 378 Newton Hall, 1585 Neil Ave., Columbus, OH 43210, USA.
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Laboratory evaluation of a dual rapid immunodiagnostic test for HIV and syphilis infection. J Clin Microbiol 2014; 53:311-3. [PMID: 25378568 DOI: 10.1128/jcm.02763-14] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
New dual tests for HIV and syphilis have been developed. Our study aimed to evaluate the laboratory performance of a dual rapid immunodiagnostic test for HIV and syphilis. Our evaluation showed high performance of this dual rapid test, which should be considered for implementation to increase screening coverage and efficiency.
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Laboratory evaluation of three rapid diagnostic tests for dual detection of HIV and Treponema pallidum antibodies. J Clin Microbiol 2014; 52:4394-7. [PMID: 25297332 DOI: 10.1128/jcm.02468-14] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The performance of three research-use-only, dual HIV and syphilis rapid diagnostic tests (RDTs) was evaluated for 150 patient serum samples and compared to reference HIV and Treponema pallidum antibody detection methods. The RDTs performed comparably, with sensitivities of 93 to 99% and specificities of 97 to 100%. The kappa statistic between the RDTs was 0.95.
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Abstract
PURPOSE OF REVIEW Genital herpes has a high global prevalence and burden of disease. This manuscript highlights recent advances in our understanding of genital herpes simplex virus (HSV) infections. RECENT FINDINGS Studies demonstrate a changing epidemiological landscape with an increasing proportion of genital herpes cases associated with HSV type 1. There is also growing evidence that the majority of infected individuals exhibit frequent, brief shedding episodes that are most often asymptomatic, which likely contribute to high HSV transmission rates. Given this finding as well as readily available serological assays, some have proposed that routine HSV screening be performed; however, this remains controversial and is not currently recommended. Host immune responses, particularly local CD4 and CD8 T cell activity, are crucial for HSV control and clearance following initial infection, during latency and after reactivation. Prior HSV immunity may also afford partial protection against HSV reinfection and disease. Although HSV vaccine trials have been disappointing to date and existing antiviral medications are limited, novel prophylactic and therapeutic modalities are currently in development. SUMMARY Although much remains unknown about genital herpes, improved knowledge of HSV epidemiology, pathogenesis and host immunity may help guide new strategies for disease prevention and control.
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Úlcera vulvar aguda o de Lipschütz: comparación de 2 casos clínicos. CLINICA E INVESTIGACION EN GINECOLOGIA Y OBSTETRICIA 2014. [DOI: 10.1016/j.gine.2012.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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31
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Protection provided by a herpes simplex virus 2 (HSV-2) glycoprotein C and D subunit antigen vaccine against genital HSV-2 infection in HSV-1-seropositive guinea pigs. J Virol 2013; 88:2000-10. [PMID: 24284325 DOI: 10.1128/jvi.03163-13] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
A prophylactic vaccine for genital herpes disease remains an elusive goal. We report the results of two studies performed collaboratively in different laboratories that assessed immunogenicity and vaccine efficacy in herpes simplex virus 1 (HSV-1)-seropositive guinea pigs immunized and subsequently challenged intravaginally with HSV-2. In study 1, HSV-2 glycoproteins C (gC2) and D (gD2) were produced in baculovirus and administered intramuscularly as monovalent or bivalent vaccines with CpG and alum. In study 2, gD2 was produced in CHO cells and given intramuscularly with monophosphoryl lipid A (MPL) and alum, or gC2 and gD2 were produced in glycoengineered Pichia pastoris and administered intramuscularly as a bivalent vaccine with Iscomatrix and alum to HSV-1-naive or -seropositive guinea pigs. In both studies, immunization boosted neutralizing antibody responses to HSV-1 and HSV-2. In study 1, immunization with gC2, gD2, or both immunogens significantly reduced the frequency of genital lesions, with the bivalent vaccine showing the greatest protection. In study 2, both vaccines were highly protective against genital disease in naive and HSV-1-seropositive animals. Comparisons between gD2 and gC2/gD2 in study 2 must be interpreted cautiously, because different adjuvants, gD2 doses, and antigen production methods were used; however, significant differences invariably favored the bivalent vaccine. Immunization of naive animals with gC2/gD2 significantly reduced the number of days of vaginal shedding of HSV-2 DNA compared with that for mock-immunized animals. Surprisingly, in both studies, immunization of HSV-1-seropositive animals had little effect on recurrent vaginal shedding of HSV-2 DNA, despite significantly reducing genital disease.
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Johnston C, Koelle DM, Wald A. Current status and prospects for development of an HSV vaccine. Vaccine 2013; 32:1553-60. [PMID: 24016811 DOI: 10.1016/j.vaccine.2013.08.066] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 06/05/2013] [Accepted: 08/17/2013] [Indexed: 12/24/2022]
Abstract
Herpes simplex virus type 2 (HSV-2) infects 530million people, is the leading cause of genital ulcer disease, and increases the risk of HIV-1 acquisition. Although several candidate vaccines have been promising in animal models, prophylactic and therapeutic vaccines have not been effective in clinical trials thus far. Null results from the most recent prophylactic glycoprotein D2 subunit vaccine trial suggest that we must reevaluate our approach to HSV-2 vaccine development. We discuss HSV-2 pathogenesis, immunity, and vaccine efforts to date, as well as the current pipeline of candidate vaccines and design of trials to evaluate new vaccine constructs.
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Affiliation(s)
- Christine Johnston
- Department of Medicine, University of Washington, Seattle, WA, United States; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
| | - David M Koelle
- Department of Medicine, University of Washington, Seattle, WA, United States; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; Department of Laboratory Medicine, University of Washington, Seattle, WA, United States; Department of Global Health, University of Washington, Seattle, WA, United States; Benaroya Research Institute, Seattle, WA, United States
| | - Anna Wald
- Department of Medicine, University of Washington, Seattle, WA, United States; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; Department of Laboratory Medicine, University of Washington, Seattle, WA, United States; Department of Epidemiology, University of Washington, Seattle, WA, United States
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The Haemophilus ducreyi Fis protein is involved in controlling expression of the lspB-lspA2 operon and other virulence factors. Infect Immun 2013; 81:4160-70. [PMID: 23980107 DOI: 10.1128/iai.00714-13] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Expression of the lspB-lspA2 operon encoding a virulence-related two-partner secretion system in Haemophilus ducreyi 35000HP is directly regulated by the CpxRA regulatory system (M. Labandeira-Rey, J. R. Mock, and E. J. Hansen, Infect. Immun. 77:3402-3411, 2009). In the present study, we show that this secretion system is also regulated by the small nucleoid-associated protein Fis. Inactivation of the H. ducreyi fis gene resulted in a reduction in expression of both the H. ducreyi LspB and LspA2 proteins. DNA microarray experiments showed that a H. ducreyi fis deletion mutant exhibited altered expression levels of genes encoding other important H. ducreyi virulence factors, including DsrA and Flp1, suggesting a possible global role for Fis in the control of virulence in this obligate human pathogen. While the H. ducreyi Fis protein has a high degree of sequence and structural similarity to the Fis proteins of other bacteria, its temporal pattern of expression was very different from that of enterobacterial Fis proteins. The use of a lacZ-based transcriptional reporter provided evidence which indicated that the H. ducreyi Fis homolog is a positive regulator of gyrB, a gene that is negatively regulated by Fis in enteric bacteria. Taken together, the Fis protein expression data and the observed regulatory effects of Fis in H. ducreyi suggest that this small DNA binding protein has a regulatory role in H. ducreyi which may differ in substantial ways from that of other Fis proteins.
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Muralidhar S, Talwar R, Anil Kumar D, Kumar J, Bala M, Khan N, Ramesh V. Genital Ulcer Disease: How Worrisome Is It Today? A Status Report from New Delhi, India. JOURNAL OF SEXUALLY TRANSMITTED DISEASES 2013; 2013:203636. [PMID: 26316954 PMCID: PMC4437428 DOI: 10.1155/2013/203636] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/11/2012] [Revised: 03/07/2013] [Accepted: 03/15/2013] [Indexed: 11/30/2022]
Abstract
Background and Objectives. Genital ulcer diseases represent a diagnostic dilemma, especially in India, where few STI clinics have access to reliable laboratory facility. The changing STI trends require that a correct diagnosis be made in order to institute appropriate treatment and formulate control policies. The objective of this study was to determine recent trends in aetiology of genital ulcers, by using accurate diagnostic tools. Methods. Specimens from 90 ulcer patients were processed for dark field microscopy, stained smears, culture for H. ducreyi, and real-time PCR. Blood samples were collected for serological tests. Results. Prevalence of GUD was 7.45 with mean age at initial sexual experience as 19.2 years. Use of condom with regular and nonregular partners was 19.5% and 42.1%, respectively. Sexual orientation was heterosexual (92.2%) or homosexual (2.2%). There were 8 cases positive for HIV (8.9%). Herpes simplex virus ulcers were the commonest, followed by syphilis and chancroid. There were no cases of donovanosis and LGV. Conclusions. A valuable contribution of this study was in validating clinical and syndromic diagnoses of genital ulcers with an accurate aetiological diagnosis. Such reliable data will aid treatment and better define control measures of common agents and help eliminate diseases amenable to elimination, like donovanosis.
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Affiliation(s)
- Sumathi Muralidhar
- Regional STD Teaching, Training & Research Centre, VMMC & Safdarjang Hospital, New Delhi 110029, India
| | - Richa Talwar
- Department of Community Medicine, Vardhman Mahavir Medical College, Safdarjang Hospital, New Delhi 110029, India
| | - Deepa Anil Kumar
- Department of Microbiology, Faculty of Dentistry, Jamia Millia Islamia University, New Delhi 110025, India
| | - Joginder Kumar
- Regional STD Teaching, Training & Research Centre, VMMC & Safdarjang Hospital, New Delhi 110029, India
| | - Manju Bala
- Regional STD Teaching, Training & Research Centre, VMMC & Safdarjang Hospital, New Delhi 110029, India
| | - Nilofar Khan
- Regional STD Teaching, Training & Research Centre, VMMC & Safdarjang Hospital, New Delhi 110029, India
| | - V. Ramesh
- Regional STD Teaching, Training & Research Centre, VMMC & Safdarjang Hospital, New Delhi 110029, India
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Mundle ST, Hernandez H, Hamberger J, Catalan J, Zhou C, Stegalkina S, Tiffany A, Kleanthous H, Delagrave S, Anderson SF. High-purity preparation of HSV-2 vaccine candidate ACAM529 is immunogenic and efficacious in vivo. PLoS One 2013; 8:e57224. [PMID: 23468943 PMCID: PMC3582571 DOI: 10.1371/journal.pone.0057224] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Accepted: 01/18/2013] [Indexed: 01/22/2023] Open
Abstract
Genital herpes is a sexually transmitted infection (STI) caused by herpes simplex virus 2 (HSV-2) and to a lesser extent herpes simplex virus 1 (HSV-1). Infection by HSV-2 is life-long and is associated with significant cost to healthcare systems and social stigma despite the highly prevalent nature of the disease. For instance, the proportion of HSV-2 seropositive to seronegative adults is approximately 1 in 5 in the US and greater than 4 in 5 in some areas of sub-Saharan Africa. The replication-defective vaccine strain virus dl5-29 was re-derived using cells appropriate for GMP manufacturing and renamed ACAM529. Immunization with dl5-29 was previously reported to be protective both in mice and in guinea pigs, however these studies were performed with vaccine that was purified using methods that cannot be scaled for manufacturing of clinical material. Here we describe methods which serve as a major step towards preparation of ACAM529 which may be suitable for testing in humans. ACAM529 can be harvested from infected cell culture of the trans-complementing cell line AV529 clone 19 (AV529-19) without mechanical cell disruption. ACAM529 may then be purified with respect to host cell DNA and proteins by a novel purification scheme, which includes a combination of endonuclease treatment, depth filtration, anion-exchange chromatography and ultrafiltration/diafiltration (UF/DF). The resultant virus retains infectivity and is ∼ 200-fold more pure with respect to host cell DNA and proteins than is ACAM529 purified by ultracentrifugation. Additionally, we describe a side-by-side comparison of chromatography-purified ACAM529 with sucrose cushion-purified ACAM529, which shows that both preparations are equally immunogenic and protective when tested in vivo.
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Affiliation(s)
- Sophia T Mundle
- Discovery North America, Sanofi Pasteur, Cambridge, Massachusetts, United States of America.
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Type-specific identification of anogenital herpes simplex virus infections by use of a commercially available nucleic acid amplification test. J Clin Microbiol 2012; 50:3466-71. [PMID: 22875892 DOI: 10.1128/jcm.01685-12] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Herpes infections are among the most common sexually transmitted infections (STI), but diagnostic methods for genital herpes have not kept pace with the movement toward molecular testing. Here, we describe an FDA-approved molecular assay that identifies and types herpes simplex virus (HSV) infections for use in routine clinical settings. Paired samples from anogenital lesions were tested using the BD ProbeTec HSV Q(x) (HSVQ(x)) system, HSV culture and, a laboratory-developed PCR assay. Family planning, obstetrics/gynecology (OB/GYN), or sexually transmitted disease (STD) clinics in the United States served as recruitment sites. Sensitivity and specificity estimates, head-to-head comparisons, measures of agreement, and latent-class analyses were performed to provide robust estimates of performance. A total of 508 participants (174 men and 334 women) with anogenital lesions were included; 260 HSV-2 and 73 HSV-1 infections were identified. No differences in test performance based on gender, clinic type, location of the lesion, or type of lesion were observed. The sensitivity of HSV-2 detection ranged from 98.4 to 100% depending on the analytical approach, while the specificity ranged from 80.6%, compared to the less sensitive culture method, to 97.0%, compared to PCR. For HSV-1, the sensitivity and specificity ranges were 96.7 to 100% and 95.1 to 99.4%, respectively. This assay may improve our ability to accurately diagnose anogenital lesions due to herpes infection.
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Incidence, prevalence, and epidemiology of herpes simplex virus-2 in HIV-1-positive and HIV-1-negative adolescents. Sex Transm Dis 2012; 39:300-5. [PMID: 22421698 DOI: 10.1097/olq.0b013e318244a90f] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Several studies have assessed risk factors associated with herpes simplex virus-2 (HSV-2) prevalence in adults; however, few have focused on HSV-2 incidence, particularly in adolescents. The objective of this study was to determine HSV-2 prevalence and incidence and associated risk factors in a HIV-1-positive and at risk HIV-1-negative adolescent population. METHODS Sera were tested for HSV-2 antibodies in 518 adolescents in the Reaching for Excellence in Adolescent Care and Health cohort at baseline and again at the final follow-up visit. Prevalence at baseline and incidence (per person years) of HSV-2 infection were calculated. Furthermore, among HIV-1-positive individuals, a subgroup analysis was performed to assess risk factors for HSV-2 infection. Conditional logistic regression was used to estimate odds ratios and P values for associations between CD4+ T-cell (CD4+) count, HIV-1 viral load (VL), and HSV-2 acquisition, adjusting for antiretroviral therapy use, other sexually transmitted infections, gender, race, and number of sexual partners. RESULTS At baseline, 179 (35%) subjects were HSV-2 positive, with an additional 47 (16%) new cases being identified during a median follow-up time of 1.95 years and an incidence rate of 7.35 cases per 100 person years. Several risk factors were associated with HSV-2 prevalence (being female, non-Hispanic, uncertainty of sexual preference, and HIV-1 positive) and incidence (using drugs, alcohol, and number of new sexual partners). Among HIV-1 positives, an increase in CD4+ count by 50 cell/mm(3) (odds ratio, 1.17; 95% CI, 1.04-1.31, P = 0.008) was associated with HSV-2 acquisition. CONCLUSIONS The high prevalence and incidence of HSV-2 infection among adolescents, compared with the general population at this age group suggests a critical need for screening and preventive programs among this targeted group.
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Lemonovich TL, Salata RA. Chancroid and Lymphogranuloma Venereum. Sex Transm Dis 2012. [DOI: 10.1002/9781118314937.ch6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Abstract
Herpes simplex virus type 2 (HSV-2) is one of the most prevalent sexually transmitted infections worldwide. In addition to recurrent genital ulcers, HSV-2 causes neonatal herpes, and it is associated with a 3-fold increased risk for HIV acquisition. Although many HSV-2 vaccines have been studied in animal models, few have reached clinical trials, and those that have been tested in humans were not consistently effective. Here, we review HSV-2 pathogenesis, with a focus on novel understanding of mucosal immunobiology of HSV-2, and vaccine efforts to date, in an attempt to stimulate thinking about future directions for development of effective prophylactic and therapeutic HSV-2 vaccines.
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Affiliation(s)
- Christine Johnston
- Department of Medicine, University of Washington, Seattle, Washington, USA.
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Gilbert M, Li X, Petric M, Krajden M, Isaac-Renton JL, Ogilvie G, Rekart ML. Using centralized laboratory data to monitor trends in herpes simplex virus type 1 and 2 infection in British Columbia and the changing etiology of genital herpes. Canadian Journal of Public Health 2011. [PMID: 21714324 DOI: 10.1007/bf03404902] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
OBJECTIVES Understanding the regional epidemiology of genital Herpes Simplex Virus (HSV) infections is important for clinical and public health practice, due to the increasing availability of type-specific serologic testing in Canada and the contribution of genital HSV-2 infection to ongoing HIV transmission. We used centralized laboratory data to describe trends in viral identifications of genital HSV in BC and assess the utility of these data for ongoing population surveillance. METHODS Records of viral identifications (1997-2005) were extracted from the Provincial Public Health Microbiology & Reference Laboratory database. Classification as genital or other site was based on documented specimen site. We conducted a descriptive analysis of trends over time, and calculated odds of HSV-1 infection among individuals with genital herpes. RESULTS Of 48,183 viral identifications, 56.8% were genital, 10.0% were peri-oral and 9.1% cutaneous; site was unknown for 22.9%. Among genital identifications, HSV-1 infection was more likely in females, younger age groups, and later time periods. The proportion of genital herpes due to HSV-1 increased over time from 31.4% to 42.8% in BC. CONCLUSIONS Our analysis of population-level laboratory data demonstrates that the proportion of genital herpes due to HSV-1 is increasing over time in BC, particularly among women and younger age groups; this has implications for clinical practice including the interpretation of type-specific serology. Provincial viral identification data are useful for monitoring the distribution of genital HSV-1 and HSV-2 infections over time. Improving clinical documentation of specimen site would improve the utility of these data.
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Affiliation(s)
- Mark Gilbert
- Division of STI/HIV Prevention and Control, BC Centre for Disease Control, 655 West 12th Avenue, Vancouver, BC V5Z 4R4.
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Ng BE, Rutherford GW, Broad AL, Moore DM. Antiviral therapy for genital herpes for prevention of HIV transmission. Hippokratia 2011. [DOI: 10.1002/14651858.cd006492.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Brian E Ng
- The University of British Columbia; School of Population and Public Health; Vancouver BC Canada
| | - George W Rutherford
- University of California, San Francisco; Global Health Sciences; 50 Beale Street Suite 1200 San Francisco California USA 94105
| | - Angela L Broad
- University of California, San Francisco; Global Health Sciences; 50 Beale Street Suite 1200 San Francisco California USA 94105
| | - David M Moore
- University of British Columbia; BC Centre for Excellence in HIV/AIDS; Vancouver British Columbia Canada
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PCR Detection of
Haemophilus ducreyi, Treponema pallidum
, and
Mycoplasma genitalium. Mol Microbiol 2011. [DOI: 10.1128/9781555816834.ch25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Tronstein E, Johnston C, Huang ML, Selke S, Magaret A, Warren T, Corey L, Wald A. Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection. JAMA 2011; 305:1441-9. [PMID: 21486977 PMCID: PMC3144252 DOI: 10.1001/jama.2011.420] [Citation(s) in RCA: 193] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
CONTEXT Since herpes simplex virus type 2 (HSV-2) antibody tests have become commercially available, an increasing number of persons have learned that they have genital herpes through serologic testing. The course of natural history of HSV-2 in asymptomatic, seropositive persons is uncertain. OBJECTIVE To evaluate the virologic and clinical course of HSV genital shedding among individuals with symptomatic and asymptomatic HSV-2 infection. DESIGN, SETTING, AND PARTICIPANTS Cohort of 498 immunocompetent HSV-2-seropositive persons enrolled in prospective studies of genital HSV shedding at the University of Washington Virology Research Clinic, Seattle, and Westover Heights Clinic, Portland, Oregon, between March 1992 and April 2008. Each participant obtained daily self-collected swabs of genital secretions for at least 30 days. MAIN OUTCOME MEASURE The rate of viral shedding measured by quantitative real-time fluorescence polymerase chain reaction for HSV DNA from genital swabs. RESULTS Herpes simplex virus type 2 was detected on 4753 of 23,683 days (20.1%; 95% confidence interval [CI], 18.3%-22.0%) in 410 persons with symptomatic genital HSV-2 infection compared with 519 of 5070 days (10.2%; 95% CI, 7.7%-13.6%) in 88 persons with asymptomatic infection (P < .001). Subclinical shedding rates were higher in persons with symptomatic infection compared with asymptomatic infection (2708 of 20,735 days [13.1%; 95% CI, 11.5%-14.6%) vs 434 of 4929 days [8.8%; 95% CI, 6.3%-11.5%]) (P < .001). However, the amount of HSV detected during subclinical shedding episodes was similar (median, 4.3 [interquartile range, 3.1-5.6] log(10) copies in the symptomatic infection group vs 4.2 [interquartile range, 2.9-5.5] in the asymptomatic infection group, P = .27). Days with lesions accounted for 2045 of 4753 days (43.0%; 95% CI, 39.8%-46.5%) with genital viral shedding among persons with symptomatic genital HSV-2 infection compared with 85 of 519 days (16.4%; 95% CI, 11.2%-23.9%) among persons with asymptomatic infection (P < .001). CONCLUSION Persons with asymptomatic HSV-2 infection shed virus in the genital tract less frequently than persons with symptomatic infection, but much of the difference is attributable to less frequent genital lesions because lesions are accompanied by frequent viral shedding.
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Affiliation(s)
| | - Christine Johnston
- Department of Medicine, University of Washington, Seattle, WA
- Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Meei-Li Huang
- Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, WA
- Department of Laboratory Medicine, University of Washington, Seattle, WA
| | - Stacy Selke
- Department of Laboratory Medicine, University of Washington, Seattle, WA
| | - Amalia Magaret
- Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, WA
- Department of Laboratory Medicine, University of Washington, Seattle, WA
- Program in Biostatistics, Fred Hutchinson Cancer Research Center, Seattle, WA
| | | | - Lawrence Corey
- Department of Medicine, University of Washington, Seattle, WA
- Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, WA
- Department of Laboratory Medicine, University of Washington, Seattle, WA
| | - Anna Wald
- Department of Medicine, University of Washington, Seattle, WA
- Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, WA
- Department of Laboratory Medicine, University of Washington, Seattle, WA
- Department of Epidemiology, University of Washington
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Abu-Raddad LJ, Schiffer JT, Ashley R, Mumtaz G, Alsallaq RA, Akala FA, Semini I, Riedner G, Wilson D. HSV-2 serology can be predictive of HIV epidemic potential and hidden sexual risk behavior in the Middle East and North Africa. Epidemics 2010; 2:173-82. [PMID: 21352788 DOI: 10.1016/j.epidem.2010.08.003] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2010] [Revised: 08/26/2010] [Accepted: 08/31/2010] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND HIV prevalence is low in the Middle East and North Africa (MENA) region, though the risk or potential for further spread in the future is not well understood. Behavioral surveys are limited in this region and when available have serious limitations in assessing the risk of HIV acquisition. We demonstrate the potential use of herpes simplex virus-2 (HSV-2) seroprevalence as a marker for HIV risk within MENA. METHODS We designed a mathematical model to assess whether HSV-2 prevalence can be predictive of future HIV spread. We also conducted a systematic literature review of HSV-2 seroprevalence studies within MENA. RESULTS We found that HSV-2 prevalence data are rather limited in this region. Prevalence is typically low among the general population but high in established core groups prone to sexually transmitted infections such as men who have sex with men and female sex workers. Our model predicts that if HSV-2 prevalence is low and stable, then the risk of future HIV epidemics is low. However, expanding or high HSV-2 prevalence (greater than about 20%), implies a risk for a considerable HIV epidemic. Based on available HSV-2 prevalence data, it is not likely that the general population in MENA is experiencing or will experience such a considerable HIV epidemic. Nevertheless, the risk for concentrated HIV epidemics among several high-risk core groups is present. CONCLUSIONS HSV-2 prevalence surveys provide a useful mechanism for identifying and corroborating populations at risk for HIV within MENA. HSV-2 serology offers an effective tool for probing hidden sexual risk behaviors in a region where quality behavioral data are limited.
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Affiliation(s)
- Laith J Abu-Raddad
- Infectious Disease Epidemiology Group, Weill Cornell Medical College-Qatar, Cornell University, Qatar Foundation, Education City, Doha, Qatar.
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Abstract
The Haemophilus ducreyi 35000HP genome encodes a homolog of the CpxRA two-component cell envelope stress response system originally characterized in Escherichia coli. CpxR, the cytoplasmic response regulator, was shown previously to be involved in repression of the expression of the lspB-lspA2 operon (M. Labandeira-Rey, J. R. Mock, and E. J. Hansen, Infect. Immun. 77:3402-3411, 2009). In the present study, the H. ducreyi CpxR and CpxA proteins were shown to closely resemble those of other well-studied bacterial species. A cpxA deletion mutant and a CpxR-overexpressing strain were used to explore the extent of the CpxRA regulon. DNA microarray and real-time reverse transcriptase (RT) PCR analyses indicated several potential regulatory targets for the H. ducreyi CpxRA two-component regulatory system. Electrophoretic mobility shift assays (EMSAs) were used to prove that H. ducreyi CpxR interacted with the promoter regions of genes encoding both known and putative virulence factors of H. ducreyi, including the lspB-lspA2 operon, the flp operon, and dsrA. Interestingly, the use of EMSAs also indicated that H. ducreyi CpxR did not bind to the promoter regions of several genes predicted to encode factors involved in the cell envelope stress response. Taken together, these data suggest that the CpxRA system in H. ducreyi, in contrast to that in E. coli, may be involved primarily in controlling expression of genes not involved in the cell envelope stress response.
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Etiology of genital ulcer disease. A prospective study of 278 cases seen in an STD clinic in Paris. Sex Transm Dis 2010; 37:153-8. [PMID: 19910862 DOI: 10.1097/olq.0b013e3181bf5a98] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES The goal of this study was to identify the causes and factors associated with genital ulcer disease (GUD) among patients attending a sexually transmitted disease (STD) clinic in Paris. METHODS This study was a prospective investigation of GUD cases. Data were collected from 1995 to 2005. In each case, a Dark Field Examination (DFE), Gram stain, inoculation onto Thayer Martin agar, Columbia agar and chocolate agar with 1% isovitalex and 20% fetal calf serum, PCR Chlamydia trachomatis (Amplicor Roche), culture for herpes simplex virus (HSV) on MRC 5 cells and PCR HSV (Argene Biosoft) were obtained from the ulceration. First Catch Urine (FCU) PCR for Chlamydia trachomatis and syphilis, HIV, HSV, and HBV serologies were also performed. RESULTS A total 278 cases of GUD were investigated, 244 (88%) in men and 34 (12%) in women. Primary syphilis accounted for 98 cases (35%), genital herpes for 74 (27%), chancroid for 8 (3%), other infections for 12 (5%). In 91 (32%) patients, no identifiable microorganism was documented. Primary syphilis was more prevalent in MSMs (P < 0.0001), while genital herpes and chancroid were significantly associated with heterosexuality (both P < 0.0001). A high level of HIV infection (27%) was found, particularly in patients with primary syphilis (33%). In the univariate analysis, no statistical difference was found between syphilis and herpes according to clinical presentation, pain being the only item slightly more frequent in herpes (P = 0.06). In the multivariable model syphilis was associated with being MSM (OR: 51.3 [95% CI: 14.7-178.7], P < 0.001) and with an ulceration diameter >10 mm (OR: 9.2 [95% CI: 2.9-30.7], P < 0.001). Genital herpes was associated with HIV infection in the subgroup of MSWs (OR: 24.4 [2.4-247.7], P = 0.007). We did not find significant differences in the clinical presentation of the ulcers according to HIV status. CONCLUSION The profound changes of the epidemiology of GUD during the decade, due to disappearance of chancroid and reemergence of infectious syphilis have led to a new distribution of pathogens, genital herpes, primary syphilis and GUD from unknown origin, accounting each for one third of cases. No clinical characteristic is predictive of the etiology, underlining the importance of performing a thorough microbiologic evaluation. Close association with HIV is still a major public health problem.
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Petrera E, Coto CE. Therapeutic effect of meliacine, an antiviral derived from Melia azedarach L., in mice genital herpetic infection. Phytother Res 2010; 23:1771-7. [PMID: 19441066 DOI: 10.1002/ptr.2850] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Since natural products are considered powerful sources of novel drug discovery, a partially purified extract (meliacine) from the leaves of Melia azedarach L., a plant used in traditional medicine in India for the treatment of several diseases, has been studied. Meliacine exhibits a potent antiviral effect against several viruses without displaying cytotoxicity. The purpose of the present study was to evaluate the therapeutic effect of intravaginal administration of meliacine in a mouse model of genital herpetic infection. BALB/c female mice were infected with MS or G strains of Herpes Simplex Virus type 2 and then treated with meliacine topically. An overall protective effect was observed. Animal survival increased, the severity of the disease was reduced, life span was extended and virus shedding in vagina fluids was diminished. In addition, meliacine reduced the amount of virus that migrated to the brain and vaginal fluids presented higher levels of IFN-gamma and TNF-alpha than untreated infected mice. These results indicate that meliacine could be an alternative therapeutic compound against HSV-2 genital infection.
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Affiliation(s)
- Erina Petrera
- Laboratorio de Virología, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, Piso 4, Intendente Güiraldes 2160, C1428EGA, Buenos Aires, Argentina.
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Regulation of expression of the Haemophilus ducreyi LspB and LspA2 proteins by CpxR. Infect Immun 2009; 77:3402-11. [PMID: 19451237 DOI: 10.1128/iai.00292-09] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The LspA1, LspA2, and LspB proteins of Haemophilus ducreyi comprise a two-partner secretion system that has been shown to be necessary for H. ducreyi to inhibit phagocytosis by immune cells in vitro. Inactivation of lspA1 resulted in increased levels of LspA2, suggesting that these two proteins are differentially controlled (C. J. Ward et al., Infect. Immun. 71:2478-2486, 2003). Expression of LspA2 but not LspA1 was shown to be both growth phase dependent and affected by the presence of fetal calf serum (FCS) in the growth medium. In addition, neither LspA1 nor LspA2 could be detected in culture supernatant fluid in the absence of FCS. DNA microarray analysis revealed that 324 H. ducreyi genes were differentially regulated after growth in the presence of FCS. Among these, the CpxRA two-component sensory transduction system was downregulated by the presence of FCS. Inactivation of cpxR resulted in increased expression of both LspB and LspA2. Electrophoretic mobility shift assays showed that a recombinant H. ducreyi CpxR protein bound the promoter region of the lspB-lspA2 operon. The cpxR and cpxA genes were shown to be part of an operon containing two additional genes in H. ducreyi 35000HP. This is the first description of a two-component sensory transduction system regulating a proven virulence factor of H. ducreyi.
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Brans R, Akhrameyeva NV, Yao F. Prevention of genital herpes simplex virus type 1 and 2 disease in mice immunized with a gD-expressing dominant-negative recombinant HSV-1. J Invest Dermatol 2009; 129:2470-9. [PMID: 19357711 DOI: 10.1038/jid.2009.86] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
CJ9-gD is a novel herpes simplex virus (HSV) type 1 recombinant virus that is completely replication-defective, expresses high-levels of HSV-1 major antigen glycoprotein D (gD), and can function in trans to inhibit replication of wild-type HSV-1 and HSV-2 in co-infected cells. Here, we show that immunization with CJ9-gD elicits strong and long-lasting humoral and Th1-like cellular immune responses against both HSV-1 and HSV-2. Mice immunized with CJ9-gD exhibited significant reductions in the extent and duration of intravaginal replication of challenge HSV-1 and HSV-2 compared with mock-immunized controls, and were completely protected from local or systemic herpetic disease after intravaginal challenge with wild-type HSV-1 or HSV-2.
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Affiliation(s)
- Richard Brans
- Department of Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA
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Does frequency of genital herpes recurrences predict risk of transmission? Further analysis of the valacyclovir transmission study. Sex Transm Dis 2008; 35:124-8. [PMID: 17921912 DOI: 10.1097/olq.0b013e31815407d7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
BACKGROUND The benefit of suppressive antiviral therapy for reducing the risk of herpes simplex virus (HSV)-2 transmission to sex partners may be enhanced if persons at high risk for transmission can be identified. OBJECTIVE To determine whether frequency of genital herpes recurrences is associated with increased risk of HSV-2 transmission. METHODS Analysis of recurrence frequency and shedding frequency (subset) among participants in a randomized controlled trial of valacyclovir 500 mg qd versus placebo for reducing the risk of HSV-2 transmission. RESULTS Overall, 1484 monogamous HSV-2-serodiscordant couples participated and 41 HSV-2 transmissions occurred during the 8-month trial; 40 were able to provide a history of recurrence frequency. The rate of recurrences per year before study entry did not differ between source partners who transmitted and those who did not, 4.8 versus 5.1, respectively. Similarly, the mean frequency of recurrences observed during the study also did not differ among those who transmitted versus those who did not for placebo recipients (4.4 vs. 4.8) or valacyclovir recipients (1.4 vs. 1.3). Among the 40 source partners who transmitted HSV-2, 8 of 27 placebo recipients and 7 of 13 valacyclovir recipients had no recurrences during the study. CONCLUSION Clinical assessment of HSV-2 disease severity as defined by the frequency of genital herpes recurrences does not predict the risk of transmission to sexual partners. Though patients with frequent recurrences are most likely to benefit clinically from suppressive therapy, frequency of recurrences is not helpful in identifying persons who are most likely to transmit HSV-2.
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