Herpes Simplex Virus Type 2 Disease Research Articles

Immunogenicity and Therapeutic Efficacy of a Sendai-Virus-Vectored HSV-2 Vaccine in Mouse and Guinea Pig Models.

To date, there is no licensed vaccine for preventing herpes simplex virus type 2 (HSV-2). The current treatment to address the infection and prevent its transmission is not always satisfactory. We constructed two recombinant vectors, one encoding HSV-2 glycoprotein D (gD, SeV-dF/HSV-2-gD) and one encoding HSV-2-infected cell protein 27 (ICP27, SeV-dF/HSV-2-ICP27), based on a replication-defective Sendai virus through reverse genetics, collectively comprising a combinatorial HSV-2 therapeutic vaccine candidate. The immunogenicity and proper immunization procedure for this vaccine were explored in a murine model. The therapeutic effect that helps prevent recurrent HSV-2 disease was evaluated in HSV-2-infected guinea pigs. Both a robust humoral immune response and a cellular immune response, characterized by the neutralizing antibody titer and the IFN-γ level, respectively, were elicited in BALB/c mice. A further study of cellular immunogenicity in mice revealed that T lymphocytes were successfully enhanced with the desirable secretion of several cytokines. In HSV-2-seropositive guinea pigs, vaccination could reduce the severity of HSV-2 in terms of recurrent lesions, duration of recurrent outbreak, and frequency of recurrence by 58.66%, 45.34%, and 45.09%, respectively, while viral shedding was also significantly inhibited in the vaccine-treated group compared to the group treated with phosphate-buffered saline. The replication-defective recombinant Sendai viruses conveying HSV-2-gD and ICP27 proteins showed great immunogenicity and potential for preventing recurrent HSV-2 disease.

The population impact of herpes simplex virus type 2 (HSV-2) vaccination on the incidence of HSV-2, HIV and genital ulcer disease in South Africa: a mathematical modelling study

Evidence suggests HSV-2 infection increases HIV acquisition risk and HIV/HSV-2 coinfection increases transmission risk of both infections. We analysed the potential impact of HSV-2 vaccination in South Africa, a high HIV/HSV-2 prevalence setting. We adapted a dynamic HIV transmission model for South Africa to incorporate HSV-2, including synergistic effects with HIV, to evaluate the impact of: (i) cohort vaccination of 9-year-olds with a prophylactic vaccine that reduces HSV-2 susceptibility; (ii) vaccination of symptomatically HSV-2-infected individuals with a therapeutic vaccine that reduces HSV shedding. An 80% efficacious prophylactic vaccine offering lifetime protection with 80% uptake could reduce HSV-2 and HIV incidence by 84.1% (95% Credibility Interval: 81.2-86.0) and 65.4% (56.5-71.6) after 40 years, respectively. This reduces to 57.4% (53.6-60.7) and 42.1% (34.1-48.1) if efficacy is 50%, 56.1% (53.4-58.3) and 41.5% (34.2-46.9) if uptake is 40%, and 29.4% (26.0-31.9) and 24.4% (19.0-28.7) if protection lasts 10 years. An 80% efficacious therapeutic vaccine offering lifetime protection with 40% coverage among symptomatic individuals could reduce HSV-2 and HIV incidence by 29.6% (21.8-40.9) and 26.4% (18.5-23.2) after 40 years, respectively. This reduces to 18.8% (13.7-26.4) and 16.9% (11.7-25.3) if efficacy is 50%, 9.7% (7.0-14.0) and 8.6% (5.8-13.4) if coverage is 20%, and 5.4% (3.8-8.0) and 5.5% (3.7-8.6) if protection lasts 2 years. Prophylactic and therapeutic vaccines offer promising approaches for reducing HSV-2 burden and could have important impact on HIV in South Africa and other high prevalence settings. WHO, NIAID.

Endogenous Retroviruses Provide Protection Against Vaginal HSV-2 Disease.

Endogenous retroviruses (ERVs) are genomic sequences that originated from retroviruses and are present in most eukaryotic genomes. Both beneficial and detrimental functions are attributed to ERVs, but whether ERVs contribute to antiviral immunity is not well understood. Here, we used herpes simplex virus type 2 (HSV-2) infection as a model and found that Toll-like receptor 7 (Tlr7 -/-) deficient mice that have high systemic levels of infectious ERVs are protected from intravaginal HSV-2 infection and disease, compared to wildtype C57BL/6 mice. We deleted the endogenous ecotropic murine leukemia virus (Emv2) locus on the Tlr7 -/- background (Emv2 -/- Tlr7 -/-) and found that Emv2 -/- Tlr7 -/- mice lose protection against HSV-2 infection. Intravaginal application of purified ERVs from Tlr7-/- mice prior to HSV-2 infection delays disease in both wildtype and highly susceptible interferon-alpha receptor-deficient (Ifnar1- /-) mice. However, intravaginal ERV treatment did not protect Emv2-/-Tlr7-/- mice from HSV-2 disease, suggesting that the protective mechanism mediated by exogenous ERV treatment may differ from that of constitutively and systemically expressed ERVs in Tlr7-/- mice. We did not observe enhanced type I interferon (IFN-I) signaling in the vaginal tissues from Tlr7-/- mice, and instead found enrichment in genes associated with extracellular matrix organization. Together, our results revealed that constitutive and/or systemic expression of ERVs protect mice against vaginal HSV-2 infection and delay disease.

Cluster of Symptomatic Graft-to-Host Transmission of Herpes Simplex Virus Type 1 in an Endothelial Keratoplasty Setting

PurposeDescemet's membrane endothelial keratoplasty (DMEK) is becoming the gold standard to treat corneal endothelial dysfunctions worldwide. Compared with conventional penetrating keratoplasty, infectious complications after DMEK are ill defined. We describe the clinical picture of 2 DMEK recipients, operated on the same day and in the same clinic, who developed atypical herpes simplex virus type 1 (HSV-1) infection in the transplant recipient eye within days post-DMEK. Because recipients received cornea tissue from 2 different donors prepared by the same eye bank, the likelihood of a common HSV-1 source was determined.DesignCase series.ParticipantsTwo DMEK recipients who developed atypical intraocular HSV-1 disease shortly after surgery and surplus cornea specimens of 6 donors.MethodsSurplus cornea donor (pre-DMEK cornea remnants and conditioned cornea storage and transport media) and recipient samples (post-DMEK aqueous humor) were assayed for HSV-1 DNA and infectious virus by real-time polymerase chain reaction (RT-PCR) and cell culture, respectively. Target-enriched whole viral genome sequencing was performed on HSV-1 DNA–positive ocular specimens.Main Outcome MeasuresClinical picture of atypical intraocular HSV-1 infection post-DMEK and presence and homology of HSV-1 genomes between ocular specimens of DMEK donors and recipients.ResultsHerpes simplex virus type 1 DNA was detected in aqueous humor and donor cornea specimens of both DMEK cases, but not in the cornea remnants of 6 randomly selected donors processed by the same eye bank. Infectious HSV-1 was isolated from the cornea remnant and corresponding culture medium of 1 cornea donor. Notably, whole-genome sequencing of virus DNA-positive specimens demonstrated exceptionally high genetic similarity between HSV-1 strains in recipient and donor specimens of both DMEK cases.ConclusionsData indicate cross-contamination of cornea grafts during DMEK preparation with subsequent graft-to-host HSV-1 transmission that caused atypical sight-threatening herpetic eye disease shortly after DMEK. Ophthalmologists should be aware that HSV-1 transmission by DMEK is possible and can lead to atypical ocular disease, a condition that can easily be prevented by taking appropriate technical and clinical measures at both eye bank and surgical levels.

Dynamics of HSV-2 infection with a therapeutic vaccine

Herpes-Simplex Virus type 2 (HSV-2) is a lifelong infection, which has infected over 400 million individuals aged 15-49 years, worldwide. While the disease can be treated with episodic and suppressive antiviral drugs to reduce the rate of recurrence (i.e., symptomatic disease) and viral shedding, none of the currently available therapies can clear the virus from the body of an infected person. A number of therapeutic vaccine platforms are currently in development in order to achieve similar effects to treatment. Due to the inadequate data from clinical trials of therapeutic vaccines, modeling efforts to quantify the impact of vaccination have been limited. In this study, we propose a compartmental deterministic model for the dynamics of HSV-2 to evaluate the effect of a potential vaccine candidate with the inclusion of a booster dose. Despite its simplicity that may not address the complexity of HSV-2 disease, the model shows that targeting symptomatic infection for vaccination is the most effective strategy in the long-term. This conclusion is based on the assumption of an optimal vaccine efficacy, conferring immunity levels that prevent viral shedding and recurrence transiently. Our model provides a framework for developing a computational system to include more heterogeneous characteristics of the disease and individuals, and investigate effectiveness and cost-effectiveness of vaccination scenarios when clinical data become available.

Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice.

Herpes simplex virus type 1 (HSV-1) is a DNA neurotropic virus, usually establishing latent infections in the trigeminal ganglia followed by periodic reactivations. Although numerous findings suggested potential links between HSV-1 and Alzheimer’s disease (AD), a causal relation has not been demonstrated yet. Hence, we set up a model of recurrent HSV-1 infection in mice undergoing repeated cycles of viral reactivation. By virological and molecular analyses we found: i) HSV-1 spreading and replication in different brain regions after thermal stress-induced virus reactivations; ii) accumulation of AD hallmarks including amyloid-β protein, tau hyperphosphorylation, and neuroinflammation markers (astrogliosis, IL-1β and IL-6). Remarkably, the progressive accumulation of AD molecular biomarkers in neocortex and hippocampus of HSV-1 infected mice, triggered by repeated virus reactivations, correlated with increasing cognitive deficits becoming irreversible after seven cycles of reactivation. Collectively, our findings provide evidence that mild and recurrent HSV-1 infections in the central nervous system produce an AD-like phenotype and suggest that they are a risk factor for AD.

Biologic interactions between HSV-2 and HIV-1 and possible implications for HSV vaccine development

Development of a safe and effective vaccine against herpes simplex virus type 2 (HSV-2) has the potential to limit the global burden of HSV-2 infection and disease, including genital ulcer disease and neonatal herpes, and is a global sexual and reproductive health priority. Another important potential benefit of an HSV-2 vaccine would be to decrease HIV infections, as HSV-2 increases the risk of HIV-1 acquisition several-fold. Acute and chronic HSV-2 infection creates ulcerations and draws dendritic cells and activated CD4+ T cells into genital mucosa. These cells are targets for HIV entry and replication. Prophylactic HSV-2 vaccines (to prevent infection) and therapeutic vaccines (to modify or treat existing infections) are currently under development. By preventing or modifying infection, an effective HSV-2 vaccine could limit HSV-associated genital mucosal inflammation and thus HIV risk. However, a vaccine might have competing effects on HIV risk depending on its mechanism of action and cell populations generated in the genital mucosa. In this article, we review biologic interactions between HSV-2 and HIV-1, consider HSV-2 vaccine development in the context of HIV risk, and discuss implications and research needs for future HSV vaccine development.

Extracts of Equisetum giganteum L and Copaifera reticulate Ducke show strong antiviral activity against the sexually transmitted pathogen herpes simplex virus type 2

Ethnopharmacological relevanceEquisetum giganteum L and Copaifera reticulate Ducke have been traditionally used by women of the Tacana tribe in the Bolivian Amazonas for genital hygiene and for treatment of genital infection/inflammation. Aim of the studyTo assess the ability of extracts from Equisetum giganteum L and Copaifera reticulate Ducke to block genital viral infection by herpes simplex virus type 2. Materials and MethodsEquisetum giganteum L and Copaifera reticulate Ducke were collected from the Amazon region of La Paz, Bolivia. Extracts were prepared and screened for anti-viral activity against herpes simplex virus type 2 (HSV-2) using both in vitro and in in vivo models of infection. ResultsEquisetum giganteum L and Copaifera reticulate Ducke efficiently blocked HSV-2 infection of cell cultures without major cell cytotoxic effects. Extracts of Equisetum giganteum L and Copaifera reticulate Ducke could prevent HSV-2 disease development when administered together with virus in a mouse model of genital HSV-2 infection. In vitro analyses revealed that both plant extracts exerted their anti-HSV-2 effects by interfering with viral cell attachment and entry, but could not block viral replication post entry. ConclusionsThese studies show that extracts of Equisetum giganteum L and Copaifera reticulate Ducke have potent antiviral activities against HSV-2 comparable to those two previously identified plants, Croton lechleri Müll. Arg. and Uncaria tomentosa (Willd. ex Schult.) DC. These studies confirm that plants used by the Tacana tribe could be explored further for the development of novel topical antiviral microbicides.

In Situ Detection of Regulatory T Cells in Human Genital Herpes Simplex Virus Type 2 (HSV-2) Reactivation and Their Influence on Spontaneous HSV-2 Reactivation.

Herpes simplex virus type 2 (HSV-2) reactivation is accompanied by a sustained influx of CD4(+) and CD8(+) T cells that persist in genital tissue for extended periods. While CD4(+) T cells have long been recognized as being present in herpetic ulcerations, their role in subclinical reactivation and persistence is less well known, especially the role of CD4(+) regulatory T cells (Tregs). We characterized the Treg (CD4(+)Foxp3(+)) population during human HSV-2 reactivation in situ in sequential genital skin biopsy specimens obtained from HSV-2-seropositive subjects at the time of lesion onset up to 8 weeks after healing. High numbers of Tregs infiltrated to the site of viral reactivation and persisted in proximity to conventional CD4(+) T cells (Tconvs) and CD8(+) T cells. Treg density peaked during the lesion stage of the reactivation. The number of Tregs from all time points (lesion, healed, 2 weeks after healing, 4 weeks after healing, and 8 weeks after healing) was significantly higher than in control biopsy specimens from unaffected skin. There was a direct correlation between HSV-2 titer and Treg density. The association of a high Treg to Tconv ratio with high viral shedding suggests that the balance between regulatory and effector T cells influences human HSV-2 disease.

Oral and Vaginal Tenofovir for Genital Herpes Simplex Virus Type 2 Shedding in Immunocompetent Women: A Double-Blind, Randomized, Cross-over Trial.

Tenofovir is a potent anti-human immunodeficiency virus (HIV) agent that decreased risk of herpes simplex virus type 2 (HSV-2) acquisition in HIV pre-exposure prophylaxis trials. Whether tenofovir has utility in established HSV-2 disease is unclear. We randomized immunocompetent women with symptomatic HSV-2 infection to oral tenofovir disoproxil fumarate (TDF)/placebo vaginal gel, oral placebo/tenofovir (TFV) vaginal gel, or double placebo (ratio 2:2:1) in a one-way cross-over trial. Women collected genital swabs twice daily for HSV PCR during 4-week lead-in and 5-week treatment phases. The primary intent-to-treat end point was within-person comparison of genital HSV shedding and lesion rates. 64 women completed the lead-in phase and were randomized. Neither TDF nor TFV gel decreased overall shedding or lesion rate in the primary analysis; TFV gel decreased quantity of HSV DNA by -0.50 (-0.86-0.13) log10 copies/mL. In the per-protocol analysis, TDF reduced shedding (relative risk [RR] = 0.74, P = .006) and lesion rates (RR = 0.75, P = .032); quantity of virus shed decreased by 0.41 log10 copies/mL. Oral TDF modestly decreased HSV shedding and lesion rate, and quantity of virus shed when used consistently. Vaginal TFV gel decreased quantity of virus shed by 60%. In contrast to effects on HSV-2 acquisition, tenofovir is unlikely to provide clinically meaningful reductions in the frequency of HSV shedding or genital lesions. NCT01448616.

Establishment of HSV1 latency in immunodeficient mice facilitates efficient in vivo reactivation.

The establishment of latent infections in sensory neurons is a remarkably effective immune evasion strategy that accounts for the widespread dissemination of life long Herpes Simplex Virus type 1 (HSV1) infections in humans. Periodic reactivation of latent virus results in asymptomatic shedding and transmission of HSV1 or recurrent disease that is usually mild but can be severe. An in-depth understanding of the mechanisms regulating the maintenance of latency and reactivation are essential for developing new approaches to block reactivation. However, the lack of a reliable mouse model that supports efficient in vivo reactivation (IVR) resulting in production of infectious HSV1 and/or disease has hampered progress. Since HSV1 reactivation is enhanced in immunosuppressed hosts, we exploited the antiviral and immunomodulatory activities of IVIG (intravenous immunoglobulins) to promote survival of latently infected immunodeficient Rag mice. Latently infected Rag mice derived by high dose (HD), but not low dose (LD), HSV1 inoculation exhibited spontaneous reactivation. Following hyperthermia stress (HS), the majority of HD inoculated mice developed HSV1 encephalitis (HSE) rapidly and synchronously, whereas for LD inoculated mice reactivated HSV1 persisted only transiently in trigeminal ganglia (Tg). T cells, but not B cells, were required to suppress spontaneous reactivation in HD inoculated latently infected mice. Transfer of HSV1 memory but not OVA specific or naïve T cells prior to HS blocked IVR, revealing the utility of this powerful Rag latency model for studying immune mechanisms involved in control of reactivation. Crossing Rag mice to various knockout strains and infecting them with wild type or mutant HSV1 strains is expected to provide novel insights into the role of specific cellular and viral genes in reactivation, thereby facilitating identification of new targets with the potential to block reactivation.

Topical SMIP-7.7, a Toll–Like Receptor 7 Agonist, Protects against Genital Herpes Simplex Virus Type-2 Disease in the Guinea Pig Model of Genital Herpes

Development of more effective therapies for genital herpes simplex virus type-2 (HSV-2) infections remains a priority. The toll-like receptors (TLR) are attractive targets for the immunomodulation of primary and recurrent genital herpes infection. The guinea pig model of genital HSV-2 disease was therefore used to evaluate the efficacy of a new TLR-7 agonist, SMIP-7.7. The effects of SMIP-7.7 at concentrations between 0.90% and 0.09% were compared to the vehicle control or Aldara(®) (3M Health Care Limited, Northridge, CA, USA) as treatment for genital HSV-2 infections. Following intravaginal inoculation of Hartley guinea pigs with 10(6) pfu HSV-2 (MS strain), animals were treated intravaginally beginning at 36 h post-infection. Animals were evaluated for acute disease, acute virus replication, recurrent disease and shedding, as well as infection of the dorsal root ganglia. Treatment with SMIP-7.7 significantly decreased mean total lesion scores during primary infection (all doses, P<0.01 compared with vehicle control, and similar to Aldara(®)). Vaginal virus titres were reduced in treated animals compared with vehicle control (P<0.001 for each treatment versus vehicle control on day 4). Treatment with SMIP-7.7 also significantly decreased the number of recurrent lesion days, the number of days with recurrent virus shedding and the infection of the dorsal root ganglia compared to the vehicle control, and was similar to Aldara(®). As opposed to Aldara(®), SMIP-7.7 did not induce fever or weight loss during treatment. SMIP-7.7 improves the outcome of primary and recurrent HSV-2 disease comparable to Aldara(®) but without some of the side effects associated with Aldara(®).

Persistence of mucosal T-cell responses to herpes simplex virus type 2 in the female genital tract.

Relatively little is known about the human T cell response to HSV-2 in the female genital tract, a major site of heterosexual HSV-2 acquisition, transmission and reactivation. In order to understand the role of local mucosal immunity in HSV-2 infection, T cell lines were expanded from serial cervical cytobrush samples from 30 HSV-2 infected women and examined for reactivity to HSV-2. Approximately 3% of the CD3+ T cells isolated from the cervix were HSV-2 specific and of these, a median of 91.3% were CD4+ while a median of 3.9% were CD8+. HSV-2 specific CD4+ T cells expanded from the cervix were not only more frequent than CD8+ T cells but also exhibited greater breadth in terms of antigenic reactivity. T cells directed at the same HSV-2 protein were often detected in serial cervical cytobrush samples and in blood. Thus, broad and persistent mucosal T cell responses to HSV-2 were detected in the female genital tract of HSV-2+ women suggesting that these cells are resident at the site of HSV-2 infection. Understanding the role of these T cells at this biologically relevant site will be central to the elucidation of adaptive immune mechanisms involved in controlling HSV-2 disease.

Herpes simplex virus type 2 and HIV disease progression: a systematic review of observational studies

BackgroundHerpes simplex virus type 2 (HSV-2) is a common co-infection among HIV-infected adults that is hypothesized to accelerate HIV disease progression.MethodsWe searched Medline, EMBASE, relevant conference proceedings (2006–12) and bibliographies of identified studies without language restriction for cohort studies examining the impact of HSV-2 on highly active antiretroviral therapy-untreated HIV disease in adults. The exposure of interest was HSV-2 seropositivity or clinical/laboratory markers of HSV-2 activity. The primary outcome was HIV disease progression, defined as antiretroviral initiation, development of AIDS/opportunistic infection, or progression to CD4 count thresholds (≤200 or ≤350 cells/mm3). Secondary outcomes included HIV plasma viral load and CD4 count.ResultsSeven studies were included. No definitive relationship was observed between HSV-2 seropositivity and time to antiretroviral initiation (n=2 studies), CD4≤350 (n=1), CD4≤200 (n=1), death (n=1), viral load (n=6) or CD4 count (n=3). Although two studies each observed trends towards accelerated progression to clinical AIDS/opportunistic infection in HSV-2 seropositives, with pooled unadjusted hazard ratio=1.85 (95% CI=1.12,3.06; I2=2%), most OIs observed in the study for which data were available can occur at high CD4 counts and may not represent HIV progression. In contrast, a single study HSV-2 disease activity found that the presence of genital HSV-2 DNA was associated with a 0.4 log copies/mL increase in HIV viral load.ConclusionsDespite an observation that HSV-2 activity is associated with increased HIV viral load, definitive evidence linking HSV-2 seropositivity to accelerated HIV disease progression is lacking. The attenuating effects of acyclovir on HIV disease progression observed in recent trials may result both from direct anti-HIV activity as well as from indirect benefits of HSV-2 suppression.

Primary Maternal Herpes Simplex Virus-1 Gingivostomatitis During Pregnancy and Neonatal Herpes: Case Series and Literature Review.

Neonatal herpes simplex virus (HSV) is a serious, life-threatening infection that is usually acquired during birth from contact with infected maternal genital secretions. Primary maternal HSV gingivostomatitis is a rare occurrence during pregnancy, and HSV type 1 (HSV-1) neonatal disease after primary maternal HSV gingivostomatitis during pregnancy has not been reported in detail. We reviewed the medical records of neonates (≤28 days of age) with a confirmed diagnosis of neonatal HSV-1 at a single pediatric center from January 1981 to January 2010 to identify cases in which the mother had primary gingivostomatitis during pregnancy or at term. Seven neonates whose mothers had primary HSV-1 gingivostomatitis during pregnancy were identified from a review of 48 neonates with laboratory-proven HSV-1 neonatal disease. Of the 7 women, 2 presented with symptoms of primary HSV-1 gingivostomatitis during the first trimester and 5 in the third trimester. Three of the neonates developed skin, eye, and mucous membrane disease, 2 developed central nervous system disease, and 2 developed disseminated disease. One of the neonates with disseminated HSV-1 disease died. Primary maternal HSV gingivostomatitis during pregnancy may lead to HSV-1 transmission to the neonate. Physicians caring for pregnant women should communicate the diagnosis of HSV gingivostomatitis to the neonate's primary provider to ensure proper surveillance, early evaluation, and prompt treatment.

Efficacy of the anti-VZV (anti-HSV3) vaccine in HSV1 and HSV2 recurrent herpes simplex disease: a prospective study

Efficacy of the anti-VZV (anti-HSV3) vaccine in HSV1 and HSV2 recurrent herpes simplex disease: a prospective study Jacqueline Le Goaster,1 Sylvie Gonzalo,2 Patrice Bour&eacute;e,1 Frederic Tangy,3 Anne-Lise Haenni41Department of Tropical Diseases, Centre Hospitalo-Universitaire (CHU), University of Paris XI, Le Kremlin Bic&ecirc;tre, 2Biomnis Laboratory, Ivry-sur-Seine, 3Retro-Virology, Centre National de Recherche Scientifique (CNRS), Pasteur Institute, Paris; 4Jacques Monod Institute, Centre National de Recherche Scientifique (CNRS), University of Paris VII, Paris, FranceBackground: The aim of this study was to evaluate the possibility of using the anti-varicella zoster virus (anti-VZV, also known as anti-HSV3) vaccine against orobuccal herpes simplex virus type 1 (HSV1) and genital herpes simplex virus type 2 (HSV2). This was suggested by study of the phylogenetic tree of members of the herpes virus family, which showed a close relationship between VZV (HSV3) and the HSV1 and HSV2 herpes viruses.Methods: The present prospective study was conducted from January 2005 through January 2011. Twenty-four patients afflicted with HSV1 and HSV2 herpes recurrences over a period of years, numbering 6&ndash;8 and more recurrences per year, agreed to receive the anti-VZV vaccine. They were compared with 26 nonvaccinated patients presenting with herpes simplex diseases 2&ndash;5 times a year. All 50 patients were documented with anti-HSV1, anti-HSV2, and anti-VZV antibody serological testing.Results: From 2005 through 2011, for the 24 anti-VZV vaccinated patients, the average number of herpes relapses decreased to 0, correlated with an increased anti-VZV antibody level and clinical recovery of all patients, whereas no improvement was observed for the 26 nonvaccinated herpes patients.Conclusion: Data for the anti-VZV serological antibody levels tested before and after anti-VZV vaccination showed a significant (P &lt; 0.001) increase among vaccinated patients. This suggests defective anti-VZV immune power in these patients. After 6 years of positive results for anti-VZV vaccine, this is a logical and fair hypothesis. We can now undertake a randomized study to confirm these findings.Keywords: HSV1/HSV2 herpes prevention, anti-VZV (HSV3) vaccine, anti-VZV vaccine therapy

Efficacy Results of a Trial of a Herpes Simplex Vaccine

BackgroundTwo previous studies of a herpes simplex virus type 2 (HSV-2) subunit vaccine containing glycoprotein D in HSV-discordant couples revealed 73% and 74% efficacy against genital disease in women who were negative for both HSV type 1 (HSV-1) and HSV-2 antibodies. Efficacy was not observed in men or HSV-1 seropositive women.MethodsWe conducted a randomized, double-blind efficacy field trial involving 8323 women 18 to 30 years of age who were negative for antibodies to HSV-1 and HSV-2. At months 0, 1, and 6, some subjects received the investigational vaccine, consisting of 20 μg of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant; control subjects received the hepatitis A vaccine, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units. The primary end point was occurrence of genital herpes disease due to either HSV-1 or HSV-2 from month 2 (1 month after dose 2) through month 20.ResultsThe HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], −29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (−8%; 95% CI, −59 to 26).ConclusionsIn a study population that was representative of the general population of HSV-1– and HSV-2–seronegative women, the investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection. (Funded by the National Institute of Allergy and Infectious Diseases and GlaxoSmithKline; ClinicalTrials.gov number, NCT00057330.)

Ocular herpes simplex virus type 1: is the cornea a reservoir for viral latency or a fast pit stop?

To present a review supporting and refuting evidence from mouse, rabbit, nonhuman primate, and human studies of herpes simplex virus type 1 (HSV-1) concerning corneal latency. More than 50 research articles on HSV-1 published in peer-reviewed journals were examined. Infectious HSV-1 has been found in mouse denervated tissues and in tissues with negative cultures from the corresponding ganglion. However, the different mouse strains have shown varied responses to different strains of HSV, making it difficult to relate such findings to humans. Rabbit studies provide excellent evidence for HSV-1 corneal latency including data on HSV-1 migration from the cornea into the corneoscleral rim and on the distribution of HSV-1 DNA in the cornea. However, the available methods for the detection of infectious HSV-1 may not be sensitive enough to detect low-level infection. Infectious HSV-1 has been successfully isolated from the tears of nonhuman primates in the absence of detectable corneal lesions. The recurrence of corneal ulcers in nonhuman primates before the appearance of infectious HSV-1 in tears suggests that the origin of the HSV-1 is the cornea, rather than the trigeminal ganglion. Human studies presented evidence of both ganglion and corneal latency. Understanding HSV-1 disease progression and the possibility of corneal latency could lead to more effective treatments for herpetic keratitis. However, it is unlikely that operational latency in the cornea will be definitively proven unless a new method with higher sensitivity for the detection of infectious virus is developed.

Zebrafish-Encoded 3-O-Sulfotransferase-3 Isoform Mediates Herpes Simplex Virus Type 1 Entry and Spread

Heparan sulfate proteoglycans modified by human glucosaminyl 3-O-sulfotransferase-3 (3-OST-3) isoform generates the cellular receptor for herpes simplex virus type 1 (HSV-1). Interestingly, the ability of zebrafish (ZF)-encoded 3-OST-3 isoform to modify heparan sulfate to mediate HSV-1 entry and cell-cell fusion has not been determined although it is predominantly expressed in ZF, a popular model organism to study viral infections. Here, we demonstrate that expression of ZF-encoded 3-OST-3 isoform renders the resistant Chinese hamster ovary (CHO-K1) cells to become susceptible for HSV-1 entry. The following lines of evidence support the important role of ZF-encoded 3-OST-3 isoform as the mediator of HSV-1 entry into CHO-K1 cells: (1) ZF 3-OST-3-expressing CHO-K1 cells were able to preferentially bind HSV-1 glycoprotein D, and (2) CHO-K1 cells expressing ZF-encoded 3-OST-3 acquire the ability to fuse with cells expressing HSV-1 glycoproteins. Finally, knocking down 3-OST-3 receptor by siRNA in ZF fibroblasts cells significantly reduced HSV-1 entry and glycoprotein D binding to cells. Taken together, our results provide novel insight into the significance of ZF 3-OST-3 isoform as an HSV-1 entry and fusion receptor and its potential involvement in the HSV-1 disease model of ZF.

Construction of, and T-helper (Th)1/Th2 immune responses to, a herpes simplex virus type 2 glycoprotein D-cytotoxic T-lymphocyte epitope DNA vaccine

Recombinant cytotoxic T lymphocyte (CTL) epitope DNA vaccines offer an attractive approach for the induction of robust cellular and humoral immune responses directed against human pathogen target antigens. To construct a pVAX-gD-CTL vector expressing the glycoprotein (g)D and gB CTL epitopes from herpes simplex virus type 2 (HSV2) and evaluate it in mice for immunogenicity and protective efficacy against intraperitoneal challenge with the HSV2 strain Sav. The gD gene transcript and gB CTL epitope were inserted into the pVAX vector to obtain the recombinant plasmid pVAX-gD-CTL. An in vitro study was then conducted to detect the expression of gD by immunocytochemistry and western blotting. BALB/c mice were immunized with this DNA vaccine, then the CTL activity and expression of anti-HSV2 gD IgG, interferon-gamma and interleukin-4 by lactate dehydrogenase release assay and ELISA, respectively. The protection given to the mice was assayed by a fatal dose of virus. The pVAX-gD-CTL vector was successfully constructed and could express gD in COS-7 cells. Immunogenicity of gD, anti-HSV2 gD neutralizing serum IgG antibody and robust Th1-polarized immune responses were found. Furthermore, mice were prophylactically protected from challenge with a high dose of HSV2. In summary, pVAX-gD-CTL vector was successfully used to elicit potent Th1-like cellular and humoral immune responses that were protective against HSV2 disease in mice.