Genital HSV-2 Infection Research Articles

A nonhuman primate model for genital herpes simplex virus 2 infection that results in vaginal vesicular lesions, virus shedding, and seroconversion.

The most commonly used animal models for evaluating the efficacy of HSV-2 candidate vaccines are mice and guinea pigs. While numerous HSV-2 vaccine candidates have been tested in these animals and were effective in reducing disease and mortality, these results did not predict the effectiveness of the vaccines in human trials. Infection of rhesus macaques rarely results in lesions or HSV-2 specific antibody responses. In seeking an animal model that better recapitulates human disease and that might be more predictive of the efficacy of prophylactic vaccines than mice and guinea pigs, we evaluated Cebus apella (C. apella), a New World primate, in an HSV-2 genital infection model. Infectious HSV-2 was cultured from vaginal swabs from all 4 animals for 9-14 days after intravaginal inoculation of HSV-2 seronegative monkeys. Two of 4 monkeys had vesicular lesions in the vagina or vulva. No neurological symptoms were noted. Recurrent lesions and HSV-2 DNA shedding after acute disease resolved was infrequent. UV irradiation of the genital area did not induce recurrent genital lesions or virus shedding. All 4 monkeys developed HSV-2 neutralizing antibodies as well as virus-specific CD4 and CD8 T cell responses. Reinfection of animals 15 to 19 months after primary infection did not result in lesions; animals had reduced virus shedding and a shorter duration of shedding compared with that during primary infection, suggesting that primary infection induced protective immunity. Primary fibroblasts from C. apella monkeys supported the growth of HSV-2 in vitro; in contrast, HSV-2 did not replicate above the titer of the input inoculum in fibroblasts from rhesus macaques. These observations suggest that the C. apella monkey has potential to serve as a model for evaluating the efficacy of prophylactic vaccines, antivirals, or monoclonal antibodies to HSV-2.

Analysis of HSV1/2 Infection Reveals an Association between HSV-2 Reactivation and Pregnancy.

The herpes simplex viruses consist of the strains, HSV-1 and HSV-2, which are prevalent worldwide and lack a definitive cure. We aimed to explore the specific characteristics of HSV 1 and 2 infections, such as differences between gender assigned at birth, age at infection, site of infection, comorbidities, and effect of pregnancy, through a data analysis. Between 2011 and 2018, the Israeli Central Virology Laboratory diagnosed 9189 samples using multiplexed real-time PCR. In addition, we extracted all of the medical data for 287 females hospitalized at the Sheba Medical Center with HSV-1 (161) or HSV-2 (126) genital infections. HSV-2 was almost absent in the orofacial samples from both genders, while in other lesion sites, HSV-2 was significantly more abundant in females than in males (p < 0.05,). HSV-2 was initially detected at puberty. In the hospitalized females' malignancies, both HSV-1 and HSV-2 were found with a non-significant difference. Simultaneously, pregnancies were more common in females who were HSV-2-positive compared with those who were HSV-1-positive (27.8% vs. 12.4%, respectively, p < 0.01). Primary infections occur more with HSV-1 than with HSV-2 (15.6% vs. 3.2%, respectively). Our findings demonstrate that genital HSV-2 infection episodes are more frequent during pregnancy, suggesting that pregnancy may serve as a risk factor for HSV-2 reactivation or infection.

Estimated global and regional economic burden of genital herpes simplex virus infection among 15–49 year-olds in 2016

BackgroundGlobally, herpes simplex virus (HSV)-2 and -1 infections contribute to a large disease burden, but their full economic consequences remain unclear. This study aims to estimate the global economic impact of genital HSV-2 and HSV-1 infection and its consequences for people with genital ulcer disease, neonatal herpes, and human immunodeficiency virus (HIV) infection attributable to HSV-2.MethodsUsing a societal perspective, the economic burden was calculated at the country level and presented by World Health Organization (WHO) regions and World-Bank income levels. The disease burden was obtained from previously published global disease burden studies in 2016 and disaggregated for 194 countries. Estimates of healthcare resource utilisation were sourced from a literature review, and online interviews were conducted with 20 experts from all 6 WHO regions. Relevant costs were obtained from the literature and estimated in 2016 international dollars (I$).ResultsBoth genital HSV-2 (I$31·2 billion) and HSV-1 (I$4·0 billion) infections and their consequences were estimated to cost I$35·3 billion globally in 2016. The major economic burden was from the Americas and Western Pacific regions combined, accounting for almost two-thirds of the global burden (I$20·8 billion). High- and upper-middle-income countries bore a large proportion of the economic burden (76·6% or I$27·0 billion). Costs were driven by the large number of HSV-2 recurrences; however, even assuming conservatively that people with symptomatic herpes have on average only one episode a year, global costs were estimated at I$16·5 billion.ConclusionsThe global costs of genital HSV infection and its consequences are substantial. HSV prevention interventions have the potential to avert a large economic burden in addition to disease burden; thus, efforts to accelerate HSV vaccine development are crucial.

Viral genomic variation and the severity of genital HSV-2 infection as quantified by shedding rate: a viral genome-wide association study.

The clinical severity of genital HSV-2 infection varies widely among infected persons with some experiencing frequent genital lesions while others are asymptomatic. The viral genital shedding rate is closely associated with and has been established as a surrogate marker of clinical severity. To assess the relationship between viral genetics and shedding, we assembled a set of 145 persons who had the severity of their genital herpes quantified through determination of their HSV genital shedding rate. An HSV-2 sample from each person was sequenced and biallelic variants among these genomes were identified. We found no association between metrics of genome-wide variation in HSV-2 and shedding rate. A viral genome-wide association study (vGWAS) identified the minor alleles of three individual unlinked variants as significantly associated with higher shedding rate (p<8.4x10-5): C44973T (A512T), a non-synonymous variant in UL22 (glycoprotein H); A74534G, a synonymous variant in UL36 (large tegument protein); and T119283C, an intergenic variant. We also found an association between the total number of minor alleles for the significant variants and shedding rate (p=6.6x10-7). These results add to a growing body of literature for HSV suggesting a connection between viral genetic variation and clinically important phenotypes of infection.

Epigallocatechin Gallate-Modified Silver Nanoparticles Show Antiviral Activity against Herpes Simplex Type 1 and 2.

(1) Background: Epigallocatechin gallate (EGCG) has been recognized as a flavonoid showing antiviral activity against various types of DNA and RNA viruses. In this work, we tested if EGCG-modified silver nanoparticles (EGCG-AgNPs) can become novel microbicides with additional adjuvant properties to treat herpes infections. (2) Methods: The anti-HSV and cytotoxic activities of EGCG-AgNPs were tested in human HaCaT and VK-2-E6/E7 keratinocytes. HSV-1/2 titers and immune responses after treatment with EGCG-AgNPs were tested in murine models of intranasal HSV-1 infection and genital HSV-2 infection. (3) Results: EGCG-AgNPs inhibited attachment and entry of HSV-1 and HSV-2 in human HaCaT and VK-2-E6/E7 keratinocytes much better than EGCG at the same concentration. Infected mice treated intranasally (HSV-1) or intravaginally (HSV-2) with EGCG-AgNPs showed lower virus titers in comparison to treatment with EGCG alone. After EGCG-AgNPs treatment, mucosal tissues showed a significant infiltration in dendritic cells and monocytes in comparison to NaCl-treated group, followed by significantly better infiltration of CD8+ T cells, NK cells and increased expression of IFN-α, IFN-γ, CXCL9 and CXCL10. (4) Conclusions: Our findings show that EGCG-AgNPs can become an effective novel antiviral microbicide with adjuvant properties to be applied upon the mucosal tissues.

A Trivalent HSV-2 gC2, gD2, gE2 Nucleoside-Modified mRNA-LNP Vaccine Provides Outstanding Protection in Mice against Genital and Non-Genital HSV-1 Infection, Comparable to the Same Antigens Derived from HSV-1.

HSV-1 disease is a significant public health burden causing orofacial, genital, cornea, and brain infection. We previously reported that a trivalent HSV-2 gC2, gD2, gE2 nucleoside-modified mRNA-lipid nanoparticle (LNP) vaccine provides excellent protection against vaginal HSV-1 infection in mice. Here, we evaluated whether this HSV-2 gC2, gD2, gE2 vaccine is as effective as a similar HSV-1 mRNA LNP vaccine containing gC1, gD1, and gE1 in the murine lip and genital infection models. Mice were immunized twice with a total mRNA dose of 1 or 10 µg. The two vaccines produced comparable HSV-1 neutralizing antibody titers, and surprisingly, the HSV-2 vaccine stimulated more potent CD8+ T-cell responses to gE1 peptides than the HSV-1 vaccine. Both vaccines provided complete protection from clinical disease in the lip model, while in the genital model, both vaccines prevented death and genital disease, but the HSV-1 vaccine reduced day two vaginal titers slightly better at the 1 µg dose. Both vaccines prevented HSV-1 DNA from reaching the trigeminal or dorsal root ganglia to a similar extent. We conclude that the trivalent HSV-2 mRNA vaccine provides outstanding protection against HSV-1 challenge at two sites and may serve as a universal prophylactic vaccine for HSV-1 and HSV-2.

Disease parameters following ocular herpes simplex virus type 1 infection are similar in male and female BALB/C mice.

Sex related differences in the incidence or severity of infection have been described for multiple viruses. With herpes simplex viruses, the best example is HSV-2 genital infection where women have a higher incidence of infection and can have more severe infections than men. HSV-1 causes several types of infections including skin and mucosal ulcers, keratitis, and encephalitis in humans that do not appear to have a strong biological sex component. Given that mouse strains differ in their MHC loci it is important to determine if sex differences occur in multiple strains of mice. Our goal was to answer two questions: Are virus related sex differences present in BALB/C mice and does virulence of the viral strain have an effect? We generated a panel of recombinant HSV-1 viruses with differing virulence phenotypes and characterized multiple clinical correlates of ocular infection in BALB/c mice. We found no sex-specific differences in blepharitis, corneal clouding, neurovirulence, and viral titers in eye washes. Sex differences in neovascularization, weight loss and eyewash titers were observed for some recombinants, but these were not consistent across the phenotypes tested for any recombinant virus. Considering these findings, we conclude that there are no significant sex specific ocular pathologies in the parameters measured, regardless of the virulence phenotype following ocular infection in BALB/c mice, suggesting that the use of both sexes is not necessary for the bulk of ocular infection studies.

Lifetime quality-adjusted life years lost due to genital herpes acquired in the United States in 2018: a mathematical modeling study

Genital herpes (GH), caused by herpes simplex virus type 1 and type 2 (HSV-1, HSV-2), is a common sexually transmitted disease associated with adverse health outcomes. Symptoms associated with GH outbreaks can be reduced by antiviral medications, but the infection is incurable and lifelong. In this study, we estimate the long-term health impacts of GH in the United States using quality-adjusted life years (QALYs) lost. We used probability trees to model the natural history of GH secondary to infection with HSV-1 and HSV-2 among people aged 18-49 years. We modelled the following outcomes to quantify the major causes of health losses following infection: symptomatic herpes outbreaks, psychosocial impacts associated with diagnosis and recurrences, urinary retention caused by sacral radiculitis, aseptic meningitis, Mollaret's meningitis, and neonatal herpes. The model was parameterized based on published literature on the natural history of GH. We summarized losses of health by computing the lifetime number of QALYs lost per genital HSV-1 and HSV-2 infection, and we combined this information with incidence estimates to compute the total lifetime number of QALYs lost due to infections acquired in 2018 in the United States. We estimated 0.05 (95% uncertainty interval (UI) 0.02-0.08) lifetime QALYs lost per incident GH infection acquired in 2018, equivalent to losing 0.05 years or about 18 days of life for one person with perfect health. The average number of QALYs lost per GH infection due to genital HSV-1 and HSV-2 was 0.01 (95% UI 0.01-0.02) and 0.05 (95% UI 0.02-0.09), respectively. The burden of genital HSV-1 is higher among women, while the burden of HSV-2 is higher among men. QALYs lost per neonatal herpes infection was estimated to be 7.93 (95% UI 6.63-9.19). At the population level, the total estimated lifetime QALYs lost as a result of GH infections acquired in 2018 was 33,100 (95% UI 12,600-67,900) due to GH in adults and 3,140 (95% UI 2,260-4,140) due to neonatal herpes. Results were most sensitive to assumptions on the magnitude of the disutility associated with post-diagnosis psychosocial distress and symptomatic recurrences. GH is associated with substantial health losses in the United States. Results from this study can be used to compare the burden of GH to other diseases, and it provides inputs that may be used in studies on the health impact and cost-effectiveness of interventions that aim to reduce the burden of GH. The Center for Disease Control and Prevention.

Viral Shedding 1 Year Following First-Episode Genital HSV-1 Infection

Herpes simplex virus type 1 (HSV-1) is the leading cause of first-episode genital herpes in many countries. To inform counseling messages regarding genital HSV-1 transmission, oral and genital viral shedding patterns among persons with first-episode genital HSV-1 infection were assessed. The trajectory of the development of HSV-specific antibody and T-cell responses was also characterized. Prospective cohort followed up for up to 2 years, with 82 participants followed up between 2013 and 2018. Participants were recruited from sexual health and primary care clinics in Seattle, Washington. Persons with laboratory-documented first-episode genital HSV-1 infection, without HIV infection or current pregnancy, were referred for enrollment. First-episode genital HSV-1 infection. Genital and oral HSV-1 shedding and lesion rates at 2 months, 11 months, and up to 2 years after initial genital HSV-1 infection. Participants self-collected oral and genital swabs for HSV polymerase chain reaction testing for 30 days at 2 and 11 months and up to 2 years after diagnosis of genital HSV-1. Blood samples were collected at serial time points to assess immune responses to HSV-1. Primary HSV-1 infection was defined as absent HSV antibody at baseline or evolving antibody profile using the University of Washington HSV Western Blot. HSV-specific T-cell responses were detected using interferon γ enzyme-linked immunospot. Among the 82 participants, the median (range) age was 26 (16-64) years, 54 (65.9%) were women, and 42 (51.2%) had primary HSV-1 infection. At 2 months, HSV-1 was detected from the genital tract in 53 participants (64.6%) and in the mouth in 24 participants (29.3%). Genital HSV-1 shedding was detected on 275 of 2264 days (12.1%) at 2 months and declined significantly to 122 of 1719 days (7.1%) at 11 months (model-predicted rate, 6.2% [95% CI, 4.3%-8.9%] at 2 months vs 3.2% [95% CI, 1.8%-5.7%] at 11 months; relative risk, 0.52 [95% CI, 0.29-0.93]). Genital lesions were rare, reported on 65 of 2497 days (2.6%) at 2 months and 72 of 1872 days (3.8%) at 11 months. Oral HSV-1 shedding was detected on 88 of 2247 days (3.9%) at 2 months. Persons with primary HSV-1 infection had a higher risk of genital shedding compared with those with nonprimary infection (model-predicted rate, 7.9% [95% CI, 5.4%-11.7%] vs 2.9% [95% CI, 1.7%-5.0%]; relative risk, 2.75 [95% CI, 1.40-5.44]). Polyfunctional HSV-specific CD4+ and CD8+ T-cell responses were maintained during the follow-up period. Genital HSV-1 shedding was frequent after first-episode genital HSV-1, particularly among those with primary infection, and declined rapidly during the first year after infection.

Identification of a βCD-Based Hyper-Branched Negatively Charged Polymer as HSV-2 and RSV Inhibitor.

Cyclodextrins and cyclodextrin derivatives were demonstrated to improve the antiviral potency of numerous drugs, but also to be endowed with intrinsic antiviral action. They are suitable building blocks for the synthesis of functionalized polymer structures with potential antiviral activity. Accordingly, four water-soluble hyper-branched beta cyclodextrin (βCD)-based anionic polymers were screened against herpes simplex virus (HSV-2), respiratory syncytial virus (RSV), rotavirus (HRoV), and influenza virus (FluVA). They were characterized by FTIR-ATR, TGA, elemental analyses, zeta-potential measurements, and potentiometric titrations, while the antiviral activity was investigated with specific in vitro assays. The polymer with the highest negative charge, pyromellitic dianhydride-linked polymer (P_PMDA), showed significant antiviral action against RSV and HSV-2, by inactivating RSV free particles and by altering HSV-2 binding to the cell. The polymer fraction with the highest molecular weight showed the strongest antiviral activity and both P_PMDA and its active fractions were not toxic for cells. Our results suggest that the polymer virucidal activity against RSV can be exploited to produce new antiviral materials to counteract the virus dissemination through the air or direct contact. Additionally, the strong HSV-2 binding inhibition along with the water solubility of P_PMDA and the acyclovir complexation potential of βCD are attractive features for developing new therapeutic topical options against genital HSV-2 infection.

HSV-2-Specific Human Female Reproductive Tract Tissue Resident Memory T Cells Recognize Diverse HSV Antigens.

Antigen-specific TRM persist and protect against skin or female reproductive tract (FRT) HSV infection. As the pathogenesis of HSV differs between humans and model organisms, we focus on humans with well-characterized recurrent genital HSV-2 infection. Human CD8+ TRM persisting at sites of healed human HSV-2 lesions have an activated phenotype but it is unclear if TRM can be cultivated in vitro. We recovered HSV-specific TRM from genital skin and ectocervix biopsies, obtained after recovery from recurrent genital HSV-2, using ex vivo activation by viral antigen. Up to several percent of local T cells were HSV-reactive ex vivo. CD4 and CD8 T cell lines were up to 50% HSV-2-specific after sorting-based enrichment. CD8 TRM displayed HLA-restricted reactivity to specific HSV-2 peptides with high functional avidities. Reactivity to defined peptides persisted locally over several month and was quite subject-specific. CD4 TRM derived from biopsies, and from an extended set of cervical cytobrush specimens, also recognized diverse HSV-2 antigens and peptides. Overall we found that HSV-2-specific TRM are abundant in the FRT between episodes of recurrent genital herpes and maintain competency for expansion. Mucosal sites are accessible for clinical monitoring during immune interventions such as therapeutic vaccination.

Characteristics of genital herpes in Bilbao (Northern Spain): 12-year retrospective study

BackgroundHerpes simplex virus type 2 (HSV-2) is the most common cause of genital herpes (GH), but genital infection by herpes simplex virus type 1 (HSV-1) is increasing. The aim of this study was to analyze and compare epidemiological characteristics of patients with GH. MethodsRetrospective study conducted from January 2004 to December 2015 in patients with GH attended at two Sexually Transmitted Diseases (STDs) medical consultation of Bilbao-Basurto Integrated Health Organisation in Northern Spain. Patient's medical history was reviewed and data of interest was analyzed. ResultsOne thousand three patients (524 male and 479 female) were reviewed. HSV-2 was detected in 74%. The proportion of HSV-1 increased during the study period, significantly in men (28% in 2004–2007 vs. 50% in 2012–2015). More female than male had HSV-1 infection (56% vs. 44%). The proportion of primary infection was higher among HSV-1 compared to HSV-2 (79% vs. 21%). Among the patients with HSV-1, primary infection was higher among men (86%) and in younger than 30 years. Recurrent GH was higher among HSV-2 infections (63%). In a multivariate model older age, geographic origin outside Spain, recurrent infection, prior contact with a partner's genital herpetic lesions, previous N. gonorrhoeae infection and prostitution were significantly associated with HSV-2 infection. ConclusionsHSV-2 was the most common causative agent of GH, but the proportion of HSV-1 increased. Overall, antecedent of STD and sexual risk behaviors were more frequent in patients with genital HSV-2 infection.

The R2 non-neuroinvasive HSV-1 vaccine affords protection from genital HSV-2 infections in a guinea pig model

Herpes simplex virus (HSV) infections are common and can cause severe illness but no vaccine is currently available. The recent failure of subunit HSV vaccines has highlighted the need for vaccines that present a diverse array of antigens, including the development of next-generation live-attenuated vaccines. However, most attenuated HSV strains propagate poorly, limiting their ability to elicit protective immune responses. A live-attenuated vaccine that replicates in non-neural tissue but is ablated for transmission into the nervous system may elicit protective immune responses without evoking neurologic complications or establishing life-long infections. Initial studies of R2, a live-attenuated vaccine that is engineered to be unable to invade the nervous system, used the guinea pig genital HSV model to evaluate the ability of R2 to replicate at the site of inoculation, cause disease and infect neural tissues. R2 was then evaluated as a vaccine using three routes of inoculation: intramuscular (IM), intradermal (ID) and intravaginal (IVag) and compared to IM administered gD2+MPL/Alum vaccine in the same model. R2 replicated in the genital tract but did not produce acute or recurrent disease and did not infect the neural tissue. The R2 vaccine-induced neutralizing antibody and decreased the severity of acute and recurrent HSV-2 disease as well as recurrent shedding. The ID route was the most effective. ID administered R2 was more effective than gD2+MPL/Alum at inducing neutralizing antibody, suppressing acute disease, and acute vaginal virus replication. R2 was especially more effective at reducing recurrent virus shedding, the most common source of HSV transmission. The live-attenuated prophylactic HSV vaccine, R2, was effective in the guinea pig model of genital HSV-2 especially when administered by the ID route. The use of live-attenuated HSV vaccines that robustly replicate in mucosal tissues but are ablated for neuroinvasion offers a promising approach for HSV vaccines.

Murine Skin-resident γδT Cells Impair the Immune Response to HSV in Skin.

HSV is an important cause of brain infection. Virus entry is often through breeches in the skin. γδT cells play an immunoprotective role in mice after corneal, genital or footpad (subcutaneous) HSV infection. Here we report that the presence of γδT cells in murine skin is associated with increased severity of herpetic disease, reduced protective cytokine responses and increased viral spread from the skin to the sensory ganglia in the zosteriform model. γδT cell-deficient (TCR δ -/-) mice displayed significantly decreased herpetic lesion severity after flank HSV infection compared to WT C57BL/6 controls at both primary and secondary skin infection sites. Viral titer at the primary skin site was similar to WT mice in γδT cell-deficient mice, but was significantly decreased in the ganglia and secondary skin site. γδT cell-deficient mice showed increased Th1 responses by both T cells and non-T cells at the primary site, and decreased T-cell Th17 responses and immune infiltration at the secondary site. Cytokine responses of epidermal and dermal γδT cells to HSV also differed in WT mice (Th1 in epidermis, and Th17 in the dermis), suggesting a functional dichotomy between these two subsets. Our data suggest that in contrast to other mouse models of HSV infection, skinresident γδT cells promote the pathogenesis of HSV in skin.

Characteristics of genital herpes in Bilbao (Northern Spain): 12-year retrospective study

BackgroundHerpes simplex virus type 2 (HSV-2) is the most common cause of genital herpes (GH), but genital infection by herpes simplex virus type 1 (HSV-1) is increasing. The aim of this study was to analyze and compare epidemiological characteristics of patients with GH. MethodsRetrospective study conducted from January 2004 to December 2015 in patients with GH attended at two Sexually Transmitted Diseases (STDs) medical consultation of Bilbao-Basurto Integrated Health Organisation in Northern Spain. Patient's medical history was reviewed and data of interest was analyzed. ResultsOne thousand three patients (524 male and 479 female) were reviewed. HSV-2 was detected in 74%. The proportion of HSV-1 increased during the study period, significantly in men (28% in 2004–2007 vs. 50% in 2012–2015). More female than male had HSV-1 infection (56% vs. 44%). The proportion of primary infection was higher among HSV-1 compared to HSV-2 (79% vs. 21%). Among the patients with HSV-1, primary infection was higher among men (86%) and in younger than 30 years. Recurrent GH was higher among HSV-2 infections (63%). In a multivariate model older age, geographic origin outside Spain, recurrent infection, prior contact with a partner's genital herpetic lesions, previous N. gonorrhoeae infection and prostitution were significantly associated with HSV-2 infection. ConclusionsHSV-2 was the most common causative agent of GH, but the proportion of HSV-1 increased. Overall, antecedent of STD and sexual risk behaviors were more frequent in patients with genital HSV-2 infection.

Herpes in Pregnancy

AbstractHerpes simplex virus infection (predominantly HSV2) in pregnancy can be a cause of maternal morbidity. The more serious cause of concern is perinatal transmission of infection resulting in neonatal morbidity and mortality. Genital HSV infection can be primary, non-primary first episode or recurrent infection. Clinical and laboratory diagnosis in pregnant women is similar to non-pregnant women. Direct viral testing (PCR) from lesion's and type specific serology are required to classify type of infection. Vertical transmission occurs during labor and delivery. The risk is higher in primary and non-primary first episode near the time of delivery. Antiviral treatment with Acyclovir or Valacyclovir is recommended for acute episode to reduce lesion duration and viral shedding. Acyclovir as suppressive therapy from 36 weeks onwards reduces clinical recurrences and need for caesarean delivery. Caesarean section reduces but does not eliminate the risk of vertical transmission and is recommended for a woman has an acute infection episode at the time of labor or within 6 weeks before delivery. Clinical management of preterm premature rupture of membranes in a woman with HSV infection should be individualized. All neonates born to these mothers should be carefully handled and monitored for development of neonatal herpes.

IL-36γ Is a Key Regulator of Neutrophil Infiltration in the Vaginal Microenvironment and Limits Neuroinvasion in Genital HSV-2 Infection.

HSV-2 is a neurotropic virus that causes a persistent, lifelong infection that increases risk for other sexually transmitted infections. The vaginal epithelium is the first line of defense against HSV-2 and coordinates the immune response through the secretion of immune mediators, including the proinflammatory cytokine IL-36γ. Previously, we showed that IL-36γ treatment promoted transient polymorphonuclear cell infiltration to the vaginal cavity and protected against lethal HSV-2 challenge. In this report, we reveal that IL-36γ specifically induces transient neutrophil infiltration but does not impact monocyte and macrophage recruitment. Using IL-36γ-/- mice in a lethal HSV-2 challenge model, we show that neutrophil counts are significantly reduced at 1 and 2 d postinfection and that KC-mediated mature neutrophil recruitment is impaired in IL-36γ-/- mice. Additionally, IL-36γ-/- mice develop genital disease more rapidly, have significantly reduced survival time, and exhibit an increased incidence of hind limb paralysis that is linked to productive HSV-2 infection in the brain stem. IL-36γ-/- mice also exhibit a significant delay in clearance of the virus from the vaginal epithelium and a more rapid spread of HSV-2 to the spinal cord, bladder, and colon. We further show that the decreased survival time and increased virus spread observed in IL-36γ-/- mice are not neutrophil-dependent, suggesting that IL-36γ may function to limit HSV-2 spread in the nervous system. Ultimately, we demonstrate that IL-36γ is a key regulator of neutrophil recruitment in the vaginal microenvironment and may function to limit HSV-2 neuroinvasion.

The Effect of Hormonal Contraception and Menstrual Cycle Timing on Genital Herpes Simplex Virus-2 Shedding and Lesions.

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. 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. 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). 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.

Synthesis of pseudoboehmite-graphene oxide for drug delivery system

Abstract Pseudoboehmite is a hydrated aluminium compound produced by sol-gel process and used in drug delivery systems. The graphene oxide is a material that allows for many possibilities application as modify agent in a ceramic structure. The global prevalence and incidence of herpes simplex virus infections (HSV-1 and HSV-2) have risen worldwide. A big problem is that most persons with genital HSV infection have not received a diagnosis. Other concerning situation is that the herpes infected patients are more susceptible to HIV infections. It is also observed that in women the HSV infection are more common than in men. Acyclovir is an efficient drug for the treatment of herpes viruses. However, the oral bioavailability of acyclovir is limited due to varying and incomplete absorption. In this work, pseudoboehmite was produced with incorporation of graphene oxide in the gel. The pseudoboehmite-graphene oxide was used in in vitro drug delivery system for acyclovir.

The HSV-1 live attenuated VC2 vaccine provides protection against HSV-2 genital infection in the guinea pig model of genital herpes

BackgroundAlthough development of an HSV vaccine is a priority there is currently no vaccine available. The recent failure of subunit vaccines suggest that presentation of more antigens via a live attenuated vaccine may be required for protection. We therefore evaluated VC2, a live attenuated HSV vaccine, engineered to be unable to enter into neuronal axons. MethodsVC2 pathogenesis was first evaluated in guinea pigs following intravaginal inoculation. VC2 was then evaluated as a prophylactic and therapeutic vaccine and compared protection to a gD2 vaccine adjuvanted with MPL/Alum in the guinea pig model of genital HSV-2. The guinea pig model allows evaluation of acute and recurrent disease, as well as vaginal shedding acutely and during episodes of recurrent activation. ResultsVC2 was significantly attenuated in guinea pigs compared to the wild type strain, 17syn+. It replicated poorly at the inoculation site, did not produce any genital disease and rarely infected the neural tissue. After prophylactic vaccination, the VC2 vaccine decreased the clinical severity of acute and recurrent HSV-2 disease and shedding and decreased the quantity of virus in the DRGs. When compared to gD2+MPL/Alum, VC2 was somewhat more effective especially as it relates to neural tissue infection. VC2 was not effective as a therapeutic vaccine. ConclusionThe live attenuated prophylactic HSV vaccine, VC2, was effective in the guinea pig model of genital HSV-2. Its decreased ability to infect neural tissues provides advantages over other live attenuated vaccines.