Herpes Simplex Virus Shedding Research Articles

Antiviral treatment with valacyclovir reduces virus shedding in saliva of Antarctic expeditioners

IntroductionReactivation of herpes viruses, such as Epstein–Barr virus (EBV), herpes simplex virus 1 (HSV1), and varicella zoster virus (VZV), increases in astronauts during spaceflight, compared with their preflight and postflight levels. Reactivations can increase the risk of associated clinical conditions, such as herpes zoster, chronic neuropathic pain, vision loss, stroke, cognitive impairment, and cold sores. Furthermore, continued viral shedding for longer periods after space travel may increase the risk of viral transmission to uninfected crew contacts, including, but not limited to, the immunocompromised and newborn infants. Thus, it is essential to develop spaceflight countermeasures to prevent herpes viral reactivations to ensure the health of crewmembers and their contacts. One such countermeasure is the prophylactic administration of an antiviral drug (valacyclovir) against the alpha herpesviruses (VZV and HSV1). To determine the effectiveness of this countermeasure, we studied the shedding of EBV, VZV, and HSV1 in Antarctic expeditioners, who have similar salivary viral shedding patterns during winter-over to astronauts during long spaceflights.MethodsThe efficacy of this antiviral drug as a countermeasure was determined using three major parameters in the saliva of expeditioners during winter-over with and without administration of this drug: (i) viral load and frequency, (ii) physiological stress biomarkers [i.e., levels of cortisol, dehydroepiandrosterone (DHEA), and amylase), and (iii) immune markers (i.e., inflammatory cytokines)]. Thirty-two volunteers from two Antarctic stations (McMurdo and South Pole) participated in this study. Participants were randomly assigned to either the treatment group (valacyclovir HCl: 1 g/day) or placebo group (oyster calcium: 500mg/day). ResultsViral shedding of EBV reduced significantly (> 24-fold) in the treatment group compared with the placebo group. HSV1 was also reduced by more than fivefold, but this was not statistically significant. No VZV shedding was observed in any of the participants. In the placebo group 50% of the saliva samples had measurable viral DNA (EBV, HSV1, or both), compared with 19% of the treatment group. There was no significant change in the ratio of cortisol to DHEA or levels of alpha-amylase, indicating that physiological stress was similar between the groups. No difference was detected in levels of salivary cytokines, except IL-10, which was found in significantly lower levels in the treatment group. DiscussionThese data indicate that valacyclovir is a safe and successful intervention to reduce EBV and HSV1 shedding in individuals subjected to extreme environments and stressors.

Asymptomatic shedding of herpes simplex virus in oral cavity

Herpes simplex virus (HSV) is a significant human pathogen. Dental surgeons and Dental Hygienists come across many patients which are not having clinical symptoms but are the carriers of the disease. The person working in the oral cavity is at high risk for getting infected and also the risk of cross-infection in the general population. Aim: In this study, we determine the prevalence of HSV qualitatively and quantitatively in the oral cavity in apparently asymptomatic patients. Study Setting: Institutional and PCR testing Labs. Methods & Materials: The study analyzed saliva samples derived from 220 individuals which were collected with sterile swabs. The traditional PCR method was done for qualitative analysis and real-time PCR for the quantitative analysis. Results: The results of qualitative analysis showed that HSV-2 was more commonly shed than HSV-1 in the oral cavity, while the infected persons showed more genomic copy numbers. Conclusion: The presence of asymptomatic shedding of HSV-2 may be an indicator of future immunosuppression which should be followed up.

Therapeutic HSV-2 vaccine decreases recurrent virus shedding and recurrent genital herpes disease

BackgroundGenital herpes simplex virus (HSV) type 2 is a common persistent infection that frequently reactivates to cause recurrent lesions and recurrent viral shedding which is incompletely controlled by antiviral therapy. GEN-003 is a candidate therapeutic vaccine containing 2 HSV-2 proteins, gD2 and ICP4, and Matrix-M2 adjuvant (M2). MethodsHSV-2 seropositive persons with genital herpes were randomized into three dose cohorts of Gen-003 (60 µg antigen/50 µg M2, 60 µg/75 µg M2 or Placebo). Three intramuscular doses 21 days apart of GEN-003 or placebo were administered. Participants obtained genital area swabs twice-daily for HSV-2 detection and monitored genital lesions for 12 months. The rates of virus shedding and lesion rates before vaccination were compared to 3 defined periods after vaccination; Days 43–71, Month 6 and Month 12. ResultsGEN-003 at a dose of 60 µg each antigen/50 µg M2 reduced HSV shedding immediately after dosing with a rate ratio of 0.58, compared to 0.75 for the GEN-003 60 µg/75 µg M2 and 1.06 for placebo. Lesion rates, recurrence rates, and duration of recurrences were also reduced. Reactogenicity was higher with the 75 µg M2 dose than the 50 µg M2 dose, specifically for pain, tenderness, malaise and fatigue. Antibody and cellular immune responses were stimulated by both doses and persisted to 12 months. ConclusionsGEN-003 vaccine manufactured with a scalable process gave results similar to those observed in prior clinical trials. GEN-003 had an acceptable safety profile and stimulated both humoral and cellular immune responses. The 60 µg antigen/50 µg M2 provided the maximal effect on virologic and clinical measures and warrants further development. (Funded by Genocea; ClinicalTrials.gov number NCT02515175).

Increased Frequency of Virus Shedding by Herpes Simplex Virus 2-Infected Guinea Pigs in the Absence of CD4+ T Lymphocytes.

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.

Increase in HSV shedding at initiation of antiretroviral therapy and decrease in shedding over time on antiretroviral therapy in HIV and HSV-2 infected persons.

HIV-infected persons with chronic herpesvirus infections may experience paradoxical worsening after initiation of antiretroviral therapy (ART), but the impact of longer term ART is unclear. We evaluated the relationships between genital herpes simplex virus (HSV) shedding and ART initiation and time on therapy in HIV and HSV-2-infected persons. Prospective observational study. Rates of HSV shedding in 45 HIV and HSV-2-infected persons on or off ART were prospectively followed over up to three, noncontiguous, 60-day periods, during which participants performed daily genital swabs for HSV detection by real-time HSV DNA PCR and reported symptoms. Initiation or discontinuation of ART was at the discretion of participants' healthcare providers. In all, 6425 daily genital swabs were obtained from 45 persons (38 men and seven women) during 105 swabbing sessions. During the three sessions, 67, 74, and 92% of persons were on ART. HSV was detected on 26.5% of days in men and 22.3% of days in women. The overall rates of genital HSV shedding were 19.4% of days in persons not on ART, 30.2% in persons within 90 days of ART initiation, and 23.3% in persons on ART for longer than 90 days. After initiation of ART, HSV shedding decreased by 2% per month, or 23% per year (RR 0.98/month on ART; P = 0.0003 in adjusted analysis). This finding was consistent after including consideration of HIV viral load and CD4 cell count. HSV shedding increased significantly shortly after ART initiation, but decreased with time on prolonged ART.

Assessment of Oral Shedding of Herpes Simplex Virus Before and After Endodontic and Fixed Partial Prosthodontics Treatment in Patients with Recurrent Herpes Simplex

Background: Herpes simplex virus type 1 (HSV-1) as a member of the herpes virus family recurs in 25% of infected patients 1 - 4 times a year. Reactivation of the virus in the oral mucosa is triggered by stress, sunray, menstruation and trauma to the face. Objectives: The current study aimed to evaluate the effect of fixed prosthetic treatment and root canal therapy on symptomatic and asymptomatic shedding of HSV-1 virus into the saliva. Methods: Twenty two patients with a history of recurrent herpes simplex infection were selected, 11 of whom underwent endodontic treatment and 11 received fixed prosthesis treatment. Saliva samples were obtained immediately before and three days after spitting method of collection. The samples were stored at -70°C and then examined via the polymerase chain reaction (PCR) technique in order to detect probable shedding of the virus. Results: In general, 72.7% (P = 0.09) and 63.6% (P = 0.09) of the samples were positive for HSV-1 in the endodontic and fixed prosthesis groups, respectively. Conclusions: The results of this study indicated that dental treatment could be considered as a risk factor for asymptomatic recurrence of HSV-1 virus in the oral cavity. Therefore, to prevent HSV infection, the use of infection control measures and prophylactic antiviral therapy is critical in immunocompromised patients.

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.

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. 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. 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. 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.

Update on Neonatal Herpes Simplex Epidemiology in the Netherlands: A Health Problem of Increasing Concern?

This article provides an update on the incidence of neonatal herpes, guideline adherence by health care professionals (HCP) and trends in genital herpes simplex virus (HSV) infection during pregnancy in the Netherlands. Questionnaires were sent to all hospitals inquiring about numbers and characteristics of neonatal and maternal HSV infections, and guideline adherence between 2012 and 2015. Longitudinal trends were investigated from 1999 onward using survey data and Perinatal Registry of the Netherlands data (Perined). Trends were smoothed with Poisson regression splines. Risk indicators for neonatal and maternal HSV infections were examined with Poisson regression analyses. Neonatal herpes incidence was 4.8/100,000 live births based on survey data (2012-2015) and 3.4/100,000 based on Perined (2012-2014). Mortality rate was 23% (7/30). Neonatal herpes incidence increased slightly over time as did the prevalence of genital HSV infection among pregnant women. Non-Western ethnicity (Rate Ratio: 1.9; 95% confidence interval: 1.5-2.5) and age <20 years (Rate Ratio: 2.3; 95% confidence interval: 1.2-4.7) were associated with genital herpes during pregnancy. In Perined, none of the neonatal herpes cases had a mother diagnosed with an active genital herpes infection during pregnancy. Preventive measures to reduce vertical herpes transmission (such as cesarean section) were less commonly reported by HCP in 2012-2015 compared with 2006-2011. Neonatal herpes incidence in the Netherlands slowly increased over the last 15 years. An increased genital HSV prevalence during pregnancy or, to lower extent, the decreased guideline adherence by HCP may be responsible. A rise in asymptomatic maternal HSV shedding is also plausible, emphasizing the challenges in preventing neonatal herpes.

The effect of hormonal contraception and menstrual cycle timing on genital herpes simplex virus-2 shedding and lesions

Background The effect of female sex hormones on herpes simplex virus (HSV)-2 shedding and lesion frequency is poorly understood. Previous studies suggest that hormonal contraception may increase the frequency of HSV-2 shedding. Methods We studied HSV-2 seropositive women who performed daily genital swabbing for HSV DNA and completed diaries for genital lesions and menses. We used Poisson mixed effects models to determine if HSV detection varied throughout the menstrual cycle, or in response to hormonal contraception. We used the Wilcoxon signed-rank test and rank-sum test to determine if lesion frequency differed by cycle phase or hormonal contraceptive use. Results In 189 women aged 19 to 46 years who collected swabs on 10,715 days and were not using hormonal contraception, HSV-2 DNA was detected on 20.9% of days in the follicular phase and 17.8% of days in the luteal phase (rate ratio, 1.19; 95% confidence interval, 1.03-1.37, P = 0.02). Genital lesions did not differ in the follicular versus luteal phase (12.8% vs. 10.7%, P = 0.07). In analyses of hormonal contraception, including 244 women, HSV-2 DNA was detected on 19.0% of days for women not using hormonal contraception and 18.3% of days for those using hormonal contraception (P = 0.50). Lesions were present on 11.1% of days for women not using hormonal contraception, and 8.7% of days for those using hormonal contraception (P = 0.66). Conclusions In women with genital HSV-2 infection who are not using hormonal contraception, the follicular phase of the cycle may be associated with a higher frequency of HSV-2 shedding compared to the luteal phase. Lesion frequency is similar during the 2 menstrual phases. Hormonal contraception use was not observed to affect genital HSV-2 DNA detection or lesions.

Virus and host-specific differences in oral human herpesvirus shedding kinetics among Ugandan women and children

Human herpesviruses (HHV) establish lifelong latent infection and are transmitted primarily via shedding at mucosal surfaces. Each HHV causes a unique spectrum of disease depending on the infected individual’s age and immunity. We collected weekly oral swabs from young children and mothers in 32 Ugandan households for a median of one year. We characterized kinetics of oral shedding during primary and chronic infection for each virus. Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and HHV-6 were shed at high rates following primary infection. The rate of oral herpes simplex virus (HSV) shedding was lower overall, and children and mothers with chronic HSV infection had lower shedding rates than children with primary infection. CMV shedding rate and viral load were higher in children with primary infection compared to children with chronic infection, and even lower in mothers with chronic infection. HHV-6 shedding rate and viral load were similar between children with primary or chronic infection, but lower in mothers. EBV shedding rate and quantity decreased less dramatically in mothers versus children, with HIV-positive mothers shedding at a higher rate than HIV-negative mothers. Each HHV has a distinct pattern of oral shedding which depends partially on the age and immune status of the host.

The effect of hormonal contraception on genital herpes simplex virus-2 shedding and lesions

The effect of hormonal contraception on genital herpes simplex virus-2 shedding and lesions

Concomitant Primary Labial and Genital Herpes Simplex I Infections

Abstract There has been a decrease in the prevalence of herpes simplex type I (HSV I) infection in adolescents in the United States while the relative number of genital infections caused by HSV I has increased. Although transmission is more likely to occur during active skin lesions, asymptomatic shedding of herpes simplex virus from oral or genital sources can lead to infection in susceptible hosts. I wish to report the acquisition of concomitant primary labial and genital HSV I infection in a man and woman from an asymptomatic woman with a history of labial HSV I infection.

An intravaginal ring that releases three antiviral agents and a contraceptive blocks SHIV-RT infection, reduces HSV-2 shedding, and suppresses hormonal cycling in rhesus macaques

Women globally need access to multipurpose prevention technologies (MPTs) that prevent human immunodeficiency virus (HIV), sexually transmitted infections that increase HIV acquisition/transmission risk, and unintended pregnancy. Seeking an MPT with activity against HIV, herpes simplex virus-2 (HSV-2), and human papillomavirus (HPV), we developed a prototype intravaginal ring (IVR), the MZCL IVR, which released the antiviral agents MIV-150, zinc acetate, and carrageenan (MZC for short) and the contraceptive levonorgestrel (LNG). Previously, we showed that an MZC gel has potent activity against immunodeficiency viruses, HSV-2, and HPV and that the MZCL (MZC with LNG) IVR releases all four components in macaques in vivo at levels associated with efficacy. Vaginal fluid from treated macaques has in vitro activity against HIV, HSV-2, and HPV. Herein, we assessed the ability of the MZCL IVR to protect macaques against repeated co-challenge with HSV-2 and SHIV-RT (simian immunodeficiency virus [SIV] containing the reverse transcriptase gene from HIV) and prevent hormonal cycling. We evaluated in vivo drug release in co-challenged macaques by measuring drug levels in blood and vaginal fluid and residual drug levels in used IVRs. The MZCL IVR significantly prevented SHIV-RT infection, reduced HSV-2 vaginal shedding, and prevented cycling. No non-nucleoside HIV reverse transcriptase inhibitor (NNRTI)-resistant SHIV was detected in macaques that became infected after continuous exposure to MZC from the IVR. Macaques wearing the MZCL IVR also had carrageenan levels in vaginal fluid expected to protect from HPV (extrapolated from mice) and LNG levels in blood associated with contraceptive efficacy. The MZCL IVR is a promising MPT candidate that warrants further development.

Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir.

Several prophylactic vaccines targeting herpes simplex virus 2 (HSV-2) have failed in the clinic to demonstrate sustained depression of viral shedding or protection from recurrences. Although these vaccines have generated high titers of neutralizing antibodies (NAbs), their induction of robust CD8 T cells has largely been unreported, even though evidence for the importance of HSV-2 antigen-specific CD8 T cells is mounting in animal models and in translational studies involving subjects with active HSV-2-specific immune responses. We developed a subunit vaccine composed of the NAb targets gD and gB and the novel T cell antigen and tegument protein UL40, and we compared this vaccine to a whole-inactivated-virus vaccine (formaldehyde-inactivated HSV-2 [FI-HSV-2]). We evaluated different formulations in combination with several Th1-inducing Toll-like receptor (TLR) agonists in vivo In mice, the TLR9 agonist cytosine-phosphate-guanine (CpG) oligodeoxynucleotide formulated in a squalene-based oil-in-water emulsion promoted most robust, functional HSV-2 antigen-specific CD8 T cell responses and high titers of neutralizing antibodies, demonstrating its superiority to vaccines adjuvanted by monophosphoryl lipid A (MPL)-alum. We further established that FI-HSV-2 alone or in combination with adjuvants as well as adjuvanted subunit vaccines were successful in the induction of NAbs and T cell responses in guinea pigs. These immunological responses were coincident with a suppression of vaginal HSV-2 shedding, low lesion scores, and a reduction in latent HSV-2 DNA in dorsal root ganglia to undetectable levels. These data support the further preclinical and clinical development of prophylactic HSV-2 vaccines that contain appropriate antigen and adjuvant components responsible for programming elevated CD8 T cell responses.IMPORTANCE Millions of people worldwide are infected with herpes simplex virus 2 (HSV-2), and to date, an efficacious prophylactic vaccine has not met the rigors of clinical trials. Attempts to develop a vaccine have focused primarily on glycoproteins necessary for HSV-2 entry as target antigens and to which the dominant neutralizing antibody response is directed during natural infection. Individuals with asymptomatic infection have exhibited T cell responses against specific HSV-2 antigens not observed in symptomatic individuals. We describe for the first time the immunogenicity profile in animal models of UL40, a novel HSV-2 T cell antigen that has been correlated with asymptomatic HSV-2 disease. Additionally, vaccine candidates adjuvanted by a robust formulation of the CpG oligonucleotide delivered in emulsion were superior to unadjuvanted or MPL-alum-adjuvanted formulations at eliciting a robust cell-mediated immune response and blocking the establishment of a latent viral reservoir in the guinea pig challenge model of HSV-2 infection.

Pregnancy Outcomes in Association with STDs including genital HSV-2 shedding in a South African Cohort Study

ObjectivesGenital herpes simplex virus-2 (HSV-2) shedding in pregnant women in association with neonatal herpes infection has been widely studied but there is limited evidence of its association with pregnancy outcomes.MethodsIn...

MZC Gel Inhibits SHIV-RT and HSV-2 in Macaque Vaginal Mucosa and SHIV-RT in Rectal Mucosa.

The Population Council's microbicide gel MZC (also known as PC-1005) containing MIV-150 and zinc acetate dihydrate (ZA) in carrageenan (CG) has shown promise as a broad-spectrum microbicide against HIV, herpes simplex virus (HSV), and human papillomavirus. Previous data show antiviral activity against these viruses in cell-based assays, prevention of vaginal and rectal simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) infection, and reduction of vaginal HSV shedding in rhesus macaques and also excellent antiviral activity against HSV and human papillomavirus in murine models. Recently, we demonstrated that MZC is safe and effective against SHIV-RT in macaque vaginal explants. Here we established models of ex vivo SHIV-RT/HSV-2 coinfection of vaginal mucosa and SHIV-RT infection of rectal mucosa in macaques (challenge of rectal mucosa with HSV-2 did not result in reproducible tissue infection), evaluated antiviral activity of MZC, and compared quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay readouts for monitoring SHIV-RT infection. MZC (at nontoxic dilutions) significantly inhibited SHIV-RT in vaginal and rectal mucosas and HSV-2 in vaginal mucosa when present during viral challenge. Analysis of SHIV-RT infection and MZC activity by 1-step simian immunodeficiency virus gag quantitative RT-PCR and p27 enzyme-linked immunosorbent assay demonstrated similar virus growth dynamics and MZC activity by both methods and higher sensitivity of quantitative RT-PCR. Our data provide more evidence that MZC is a promising dual compartment multipurpose prevention technology candidate.

Effect of Pritelivir Compared With Valacyclovir on Genital HSV-2 Shedding in Patients With Frequent Recurrences

Current therapy of herpes infections relies on nucleoside analogues. Pritelivir is a well-tolerated novel herpes simplex virus (HSV) helicase-primase inhibitor that reduced genital shedding and lesions. To compare the efficacy of pritelivir with valacyclovir for suppression of genital HSV-2 infection. A phase 2, randomized, double-blind, crossover clinical trial at clinical research centers in 4 US cities (October 2012-July 2013) compared daily oral doses of 100 mg of pritelivir with 500 mg of valacyclovir. The planned sample size was 98 adults, allowing for detection of a 50% reduction in viral shedding between the study treatments. Healthy adults with 4 to 9 annual genital HSV-2 recurrences were eligible. 45 participants were randomized to receive pritelivir [corrected] and 46 to receive valacyclovir first when the US Food and Drug Administration placed the trial on clinical hold based on findings in a concurrent nonclinical toxicity study, and the sponsor terminated the study. Participants took the first drug for 28 days followed by 28 days of washout before taking the second drug for 28 days. Throughout treatment, the participants collected genital swabs 4 times daily for testing by HSV polymerase chain reaction assays. The primary end point was within-participant genital HSV shedding while receiving pritelivir compared with valacyclovir. Secondary end points included the quantity of HSV in positive swabs and the frequency of genital lesions and shedding episodes. Of the 91 randomized participants (median age, 48 years; 57 women [63%]), 56 had completed both treatment periods at the time of the study's termination. In intent-to-treat analyses, HSV shedding was detected in 2.4% (173 of 7276 ) of swabs during pritelivir treatment compared with 5.3% (392 of 7453) during valacyclovir treatment (relative risk [RR], 0.42 [corrected]; 95% CI, 0.21 to 0.82; P = .01). In swabs with HSV, the mean quantity of HSV was 3.2 log10 copies/mL during pritelivir treatment vs 3.7 log10 copies/mL during valacyclovir treatment (difference, -0.1; 95% CI, -0.6 to 0.5; P = .83). Genital lesions were present on 1.9% of days in the pritelivir group vs 3.9% in the valacyclovir group (RR, 0.40; 95% CI, 0.17-0.96; P = .04). The frequency of shedding episodes did not differ by group, with 1.3 per person-month for pritelivir and 1.6 per person-month for valacyclovir (RR, 0.80; 95% CI, 0.52 to 1.22; P = .29). Treatment-emergent adverse events occurred in 62.3% of participants in the pritelivir group and 69.2% of participants in the valacyclovir group. Among adults with frequently recurring genital HSV-2, the use of pritelivir compared with valacyclovir resulted in a lower percentage of swabs with HSV detection over 28 days. Further research is needed to assess longer-term efficacy and safety. clinicaltrials.gov Identifier: NCT01658826.

Longitudinal Viral Dynamics in Semen During Early HIV Infection.

Multiple viruses coinfect the male genital tract, influencing each other’s replication and perhaps affecting human immunodeficiency virus (HIV) pathogenesis and disease progression. This study included 453 longitudinal seminal samples from 195 HIV-infected men from the San Diego Primary Infection Resource Consortium and 67 seminal samples from HIV-negative healthy controls. Seminal HIV RNA and DNA from 7 human herpesviruses (HHVs) were measured by real-time polymerase chain reaction. Longitudinal shedding rates were determined by Kaplan-Meier survival analysis. Predictors of viral shedding were determined using backwards selection in a multivariable generalized estimating equation model. HIV-infected participants presented significantly increased rates of seminal HHV shedding compared with HIV-uninfected controls. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) were the most commonly detected HHV in semen of HIV-infected participants. Persistent shedding was more common for CMV and EBV when compared to other HHVs. With exception of HHV-7, HHV shedding was not significantly influenced by HIV RNA levels, CD4+ cell counts, or antiretroviral therapy. Presence of CMV, EBV, and herpes simplex virus (HSV) were independent predictors of genital HIV RNA shedding after adjusting for plasma HIV RNA and longitudinal measurements. Seminal replication of multiple HHVs is common in our HIV primary infection cohort. Genital replication of CMV and EBV was the most common and was significantly associated with seminal HIV RNA shedding. Prevalence of HSV shedding was lower and mostly intermittent, but its association with seminal HIV RNA was the strongest. Understanding the complex viral milieu in semen is important for HIV transmission but might also play a role in HIV pathogenesis and disease progression.

HLA Class I and II alleles, heterozygosity and HLA-KIR interactions are associated with rates of genital HSV shedding and lesions.

Variation at HLA and KIR loci is associated with the severity of viral infections. To assess associations of genital HSV-2 infection with human HLA and KIR genetic loci, we measured the frequencies of genital HSV DNA detection and of genital lesions in HSV-2 seropositive persons. We followed 267 HSV-2 seropositive persons who collected daily genital swabs and recorded lesions for ≥30 days. All persons were laboratory- documented as HIV-seronegative, and all were Caucasian by self-report. HSV detection rate and lesion frequency were compared by genotype using Poisson regression. Overall, HSV was detected on 19.1% of days and lesions on 11.6% of days. The presence of HLA-A*01 was directly associated with HSV detection frequency while the presence of HLA-C*12 was inversely associated with HSV detection frequency. The presence of HLA-A*01 was directly associated with lesion rate, while HLA-A*26, -C*01 and -DQB1*0106 were associated with decreased lesions. We observed an interaction between the absence of both 2DS4del and HLA-Bw4 and higher lesion rate. Heterozygosity of HLA was also associated with reduced lesion frequency. Immune control of genital HSV infection relies on multiple interacting immunogenetic elements, including epistatic interactions between HLA and KIR.

Mathematical Modeling Predicts that Increased HSV-2 Shedding in HIV-1 Infected Persons Is Due to Poor Immunologic Control in Ganglia and Genital Mucosa.

A signature feature of HIV infection is poor control of herpes virus infections, which reactivate from latency and cause opportunistic infections. While the general mechanism underlying this observation is deficient CD4+T-cell function, it is unknown whether increased severity of herpes virus infections is due primarily to poor immune control in latent or lytic sites of infection, or whether CD4+ immunodeficiency leads to more critical downstream deficits in humoral or cell-mediated immunologic responses. Here we compare genital shedding patterns of herpes simplex virus-2 (HSV-2) in 98 HIV infected and 98 HIV uninfected men matched on length of infection, HSV-1 serostatus and nationality. We demonstrate that high copy HSV-2 shedding is more frequent in HIV positive men, particularly in participants with CD4+ T-cell count <200/μL. Genital shedding is more frequent due to higher rate of shedding episodes, as well as a higher proportion of prolonged shedding episodes. Peak episode viral load was not found to differ between HIV infected and uninfected participants regardless of CD4+ T-cell count. We simulate a mathematical model which recapitulates these findings and identifies that rate of HSV-2 release from neural tissue increases, duration of mucosal cytolytic immune protection decreases, and cell-free viral lifespan increases in HIV infected participants. These results suggest that increased HSV-2 shedding in HIV infected persons may be caused by impaired immune function in both latent and lytic tissue compartments, with deficits in clearance of HSV-2 infected cells and extracellular virus.