Primary Genital Infection Research Articles

Management of Genital Herpes in Pregnancy: ACOG Practice Bulletin Summary, Number 220.

Genital herpes simplex virus (HSV) infection during pregnancy poses a risk to the developing fetus and newborn. Genital herpes is common in the United States. Among 14- to 49-year-old females, the prevalence of HSV-2 infection is 15.9%. However, the prevalence of genital herpes infection is higher than that because genital herpes is also caused by HSV-1 (1). Because many women of childbearing age are infected or will be infected with HSV, the risk of maternal transmission of this virus to the fetus or newborn is a major health concern. This document has been revised to include that for women with a primary or nonprimary first-episode genital HSV infection during the third trimester of pregnancy, cesarean delivery may be offered due to the possibility of prolonged viral shedding.

Management of Genital Herpes in Pregnancy: ACOG Practice Bulletinacog Practice Bulletin, Number 220.

Genital herpes simplex virus (HSV) infection during pregnancy poses a risk to the developing fetus and newborn. Genital herpes is common in the United States. Among 14- to 49-year-old females, the prevalence of HSV-2 infection is 15.9%. However, the prevalence of genital herpes infection is higher than that because genital herpes is also caused by HSV-1 (). Because many women of childbearing age are infected or will be infected with HSV, the risk of maternal transmission of this virus to the fetus or newborn is a major health concern. This document has been revised to include that for women with a primary or nonprimary first-episode genital HSV infection during the third trimester of pregnancy, cesarean delivery may be offered due to the possibility of prolonged viral shedding.

Effective clearance of Chlamydia from the female reproductive tract in the absence of T-bet+ Th1 cells

Abstract Protective immune responses to Chlamydia infection within the female reproductive tract (FRT) are incompletely understood. MHC class II-restricted CD4 Th1 responses are thought to be vital for bacterial clearance, due to their capacity to secrete IFN-γ. However, other studies suggest protective or pathogenic roles for additional CD4 T helper subsets. We used a variety of gene-deficient mice to re-examine bacterial clearance following primary genital infection of C57BL/6 mice with Chlamydia muridarum. As seen previously, IFN-γ-, and IFN-γR-deficient mice resolved much of FRT infection, but experienced systemic dissemination and 100% mortality with an average median survival of approximately 4 weeks. Mice lacking the Th1 subset defining transcription factor T-bet or the Th2 transcription factor STAT6 both effectively cleared infection from the reproductive tract, suggesting that neither Th1 nor Th2 cells are essential for local bacterial control. In contrast, RORγt mutant mice selectively deficient in Th17 responses exhibited a week delay in clearance compared to wild-type mice. Th17 subset markers were not observed to be upregulated in T-bet−/− mice and markers of Th1 subsets were minimally upregulated in RORγt mutant mice, indicating that compensation between these subsets does not explain bacterial clearance. In conclusion, timely local clearance of Chlamydia muridarum from the reproductive tract requires Th17 CD4 T cells, but will ultimately clear independent of classical T-bet+ Th1 and RORγt+ Th17 cells individually. Studies are underway to examine which alternative CD4 T cell mechanisms contribute to bacterial clearance within the FRT.

Transcriptional Analysis of the Guinea Pig Mucosal Immune Response to Intravaginal Infection with Herpes Simplex Virus Type 2

Genital herpes infection in guinea pigs closely models human infection but tools for immune characterization are limited. Immunity to HSV infection at the vaginal epithelial surface was characterized in guinea pigs using PCR-based array analysis of vaginal swab samples. IFNγ was one of the most significantly upregulated genes throughout the infection and over 40% of genes with significantly altered expression were linked to IFNγ based on INTERFEROME analysis. IFNγ transcripts and biologically active IFNγ at the genital mucosa were confirmed by RTPCR and IFNγ reporter cells. Gene ontology analysis revealed activation of many biological processes related to genital immunity shared by humans and mice demonstrating the similarities of the local immune response to primary genital HSV-2 infection in guinea pigs and other established models. This transcription-based array will be useful for dissection of immunity during reactivation from latency, an infection outcome that is not well recapitulated by other animal models.

Novel Role for Interleukin-17 in Enhancing Type 1 Helper T Cell Immunity in the Female Genital Tract following Mucosal Herpes Simplex Virus 2 Vaccination.

It is well established that interferon gamma (IFN-γ) production by CD4+ T cells is critical for antiviral immunity against herpes simplex virus 2 (HSV-2) genital infection. However, the role of interleukin-17A (IL-17A) production by CD4+ T cells in HSV-2 antiviral immunity is yet to be elucidated. Here we demonstrate that IL-17A plays an important role in enhancing antiviral T helper type 1 (Th1) responses in the female genital tract (FGT) and is essential for effective protection conferred by HSV-2 vaccination. While IL-17A did not play a critical role during primary genital HSV-2 infection, seen by lack of differences in susceptibility between IL-17A-deficient (IL-17A-/-) and wild-type (WT) C57BL/6 mice, it was critical for mediating antiviral responses after challenge/reexposure. Compared to WT mice, IL-17A-/- mice (i) infected intravaginally and reexposed or (ii) vaccinated intranasally and challenged intravaginally demonstrated poor outcomes. Following intravaginal HSV-2 reexposure or challenge, vaccinated IL-17A-/- mice had significantly higher mortality, greater disease severity, higher viral shedding, and higher levels of proinflammatory cytokines and chemokines in vaginal secretions. Furthermore, IL-17A-/- mice had impaired Th1 cell responses after challenge/reexposure, with significantly lower proportions of vaginal IFN-γ+ CD4+ T cells. The impaired Th1 cell responses in IL-17A-/- mice coincided with smaller populations of IFN-γ+ CD4+ tissue resident memory T (TRM) cells in the genital tract postimmunization. Taken together, these findings describe a novel role for IL-17A in regulating antiviral IFN-γ+ Th1 cell immunity in the vaginal tract. This strategy could be exploited to enhance antiviral immunity following HSV-2 vaccination.IMPORTANCE T helper type 1 (Th1) immunity, specifically interferon gamma (IFN-γ) production by CD4+ T cells, is critical for protection against genital herpesvirus (HSV-2) infection, and enhancing this response can potentially help improve disease outcomes. Our study demonstrated that interleukin-17A (IL-17A) plays an essential role in enhancing antiviral Th1 responses in the female genital tract (FGT). We found that in the absence of IL-17A, preexposed and vaccinated mice showed poor disease outcomes and were unable to overcome HSV-2 reexposure/challenge. IL-17A-deficient mice (IL-17A-/-) had smaller populations of IFN-γ+ CD4+ tissue resident memory T (TRM) cells in the genital tract postimmunization than did wild-type (WT) mice, which coincided with attenuated Th1 responses postchallenge. This has important implications for developing effective vaccines against HSV-2, as we propose that strategies inducing IL-17A in the genital tract may promote more effective Th1 cell immunity and better overall protection.

Co-infection of human herpesvirus type 2 (HHV-2) and human immunodeficiency virus (HIV) among pregnant women in Rio de Janeiro, Brazil

ABSTRACTPregnant women who are infected with the Human Immunodeficiency Virus (HIV) are particularly vulnerable to severe and recurrent infections with Human Herpesvirus 2 (HHV-2). Neonatal transmission of HHV-2 has been associated with malformations and neurological sequelae in infants, which makes it very important to perform antenatal monitoring for genital herpes. In the study, 134 pregnant women infected with HIV were tested for HHV-2 IgM and IgG using an enzyme-linked immunosorbent assay (ELISA) and had HHV-2 DNA analyzed by Real Time Polymerase Chain Reaction (qPCR). Fisher’s exact test was applied to analyze the epidemiological dates (p < 0.05). A total of 59.7% of the pregnant women infected with HIV had HHV-2 IgG and 3.75% of them showed HHV-2 viremia. HHV-2 IgM was found in 6% of the pregnant women and 25% of them had HHV-2 viremia. The risk factors associated with HHV-2 seropositive were age under 20 and a CD4/CD8 ratio > 1. Our study found high HHV-2/HIV coinfection prevalence and HHV-2 viremia among patients with recurrent and primary genital infection, reinforcing the need of prevention and control of HHV-2 infection in order to avoid this virus transmission.

Herpes simplex virus specific T cell response in a cohort with primary genital infection correlates inversely with frequency of subsequent recurrences

ObjectivesDuring the last decades, a changing epidemiological pattern of genital herpes simplex virus (HSV) infection has emerged. Primary infection is now caused as often by HSV-1 as by HSV-2. Once...

Laboratory diagnosis and epidemiology of herpes simplex 1 and 2 genital infections.

Herpes simplex virus types 1 and 2 are the main cause of genital ulcers worldwide. Although herpes simplex virus type 2 is the major cause of genital lesions, herpes simplex virus type 1 accounts for half of new cases in developed countries. Herpes simplex virus type 2 seroprevalence rises with sexual activity from adolescence through adulthood. Slovenian data in a high-risk population shows 16% seroprevalence of HSV-2. HSV-1 and HSV-2 DNA in genital swabs was detected in 19% and 20.7%, respectively. In most cases, genital herpes is asymptomatic. Primary genital infection with herpes simplex virus types 1 and 2 can be manifested by a severe clinical picture, involving the vesicular skin and mucosal changes and ulcerative lesions of the vulva, vagina, and cervix in women and in the genital region in men. Direct methods of viral genome detection are recommended in the acute stage of primary and recurrent infections when manifest ulcers or lesions are evident. Serological testing is recommended as an aid in diagnosing genital herpes in patients with reinfection in atypical or already healed lesions. When herpes lesions are present, all sexual activities should be avoided to prevent transmission of infection. Antiviral drugs can reduce viral shedding and thus reduce the risk of sexual transmission of the virus.

Novel rat models to study primary genital herpes simplex virus-2 infection.

In this study we describe that six rat models (SD, WIST, LEW, BN, F344 and DA) are susceptible to intravaginal herpes simplex virus-2 (HSV-2) infection after pre-treatment with progesterone. At a virus dose of 5×10(6) PFU of HSV-2, all rat models were infected presenting anti-HSV-2 antibodies, infectious virus in vaginal washes, and HSV-2 DNA genome copies in lumbosacral dorsal root ganglia and the spinal cord. Most of the LEW, BN, F344, and DA rats succumbed in systemic progressive symptoms at day 8-14 post infection, but presented no or mild genital inflammation while SD and WIST rats were mostly infected asymptomatically. Infected SD rats did not reactivate HSV-2 spontaneously or after cortisone treatment. In an HSV-2 virus dose reduction study, F344 rats were shown to be most susceptible. We also investigated whether an attenuated HSV-1 strain (KOS321) given intravaginally, could protect from a subsequent HSV-2 infection. All LEW, BN, and F344 rats survived a primary HSV-1 infection and no neuronal infection was established. In BN and F344 rats, anti-HSV-1 antibodies were readily detected while LEW rats were seronegative. In contrast to naïve LEW, BN, and F344 rats where only 3 of 18 animals survived 5×10(6) PFU of HSV-2, 23 of 25 previously HSV-1 infected rats survived a challenge with HSV-2. The described models provide a new approach to investigate protective effects of anti-viral microbicides and vaccine candidates, as well as to study asymptomatic primary genital HSV-2 infection.

TNF receptor 2 on CD8 T cells and TNF receptor 1 on non-CD8 T cells mediate upper genital tract pathology following primary genital Chlamydia muridarum infection (MUC7P.764)

Abstract We recently demonstrated that pathogenesis in the upper genital tract (UGT) following primary vaginal Chlamydia muridarum infection in mice is dependent upon TNF-alpha production and antigen-specific CD8 T cells. In this study, we evaluated the contribution of TNF receptor 1 (TNFR1) and TNFR2 to UGT pathogenesis following primary intravaginal C. muridarum infection (5X104 IFU/mouse), using depo-provera ® treated mice deficient in TNFR1 (TNFR1 KO), TNFR2 (TNFR2 KO), or TNFR1 and 2 (TNFR1/2 DKO), and the corresponding C57BL/6J wild type (WT) mice. All groups (n=8) of mice displayed comparable chlamydial clearance, antigen-specific cytokine response, and serum anti-chlamydial antibody following primary bacterial inoculation. On day 80 after primary inoculation, TNFR1 KO, TNFR2 KO, and TNFR1/2 DKO mice displayed significantly reduced oviduct pathology (hydrosalpinx), when compared to WT mice, suggesting that both TNFR1 and TNFR2 contribute significantly to oviduct pathology. Repletion of wild type or TNFR1 KO CD8 T cells did not enhance pathology significantly in TNFR1 KO mice. On the other hand, repletion of WT, but not TNFR2 KO, CD8 T cells enhanced oviduct pathology to WT levels in TNFR2 KO mice. Collectively, these results suggest that TNFR2 on CD8 T cells and TNFR1 on non-CD8 T cells mediate UGT pathology following primary genital chlamydial infection.

Recurrent Herpes Simplex Virus Type-2 Meningitis in an Adolescent Girl

【Herpes simplex virus type 2 (HSV2) meningitis primarily develops during or following a primary genital HSV2 infection that was acquired from sexual contact or through the birth canal during delivery from mother. We describe a 15 year old virgin without history of previous herpes simplex infection who developed 2 episodes of HSV2 meningitis. Although recurrent meningitis due to HSV is primarily seen in young or sexually active adults. HSV2 meningitis should be in the differential diagnosis of recurrent meningitis in adolescent patients.】

The Scarlet H

The Scarlet H

TNF-alpha receptors 1 and 2 contribute to the development of upper genital tract pathology following primary genital chlamydia muridarum infection in mice (P3200)

Abstract Chlamydia is the leading cause of sexually transmitted disease worldwide and causes serious pathologies in the upper reproductive tract. In this study, we evaluated the contribution of TNF receptor 1 (TNFR1) and TNFR2 to upper genital tract pathogenesis following primary intravaginal chlamydial infection in mice deficient in TNFR1 (TNFR1 KO), TNFR2 (TNFR2 KO), or TNFR1 and 2 (TNFR1/2 DKO), and the corresponding C57BL/6J wild type mice. All groups (n=8) of mice displayed comparable chlamydial clearance following primary bacterial inoculation. The production of IFN-gamma, IL-5, TNF-alpha, and IL-1 beta in the genital tracts, draining iliac lymph nodes, and spleens on day 9 following inoculation were comparable in all the groups. Serum anti-Chlamydia total Ab, IgG2c, and IgG1 response on days 14 and 60 following primary inoculation were comparable in all the groups. On day 80 after primary incoluation, TNFR1 KO, TNFR2 KO, and TNFR1/2 DKO mice displayed significantly reduced hydrosalpinx (6 %, 44%, and 0% oviducts, respectively), when compared to C57BL/6J mice (75% oviducts). Anti-Chlamydia antibody response and bacterial clearance following secondary intravaginal C. muridarum infection was comparable in all groups of mice. Collectively, these results suggest that TNFR1 and TNFR2 do not contribute significantly to chlamydial clearance, but both TNFR1 and TNFR2, with a dominant role for TNFR1, contribute to the UGT pathology following primary genital chlamydial infection.

Guidance on Management of Asymptomatic Neonates Born to Women With Active Genital Herpes Lesions

Herpes simplex virus (HSV) infection of the neonate is uncommon, but genital herpes infections in adults are very common. Thus, although treating an infant with neonatal herpes is a relatively rare occurrence, managing infants potentially exposed to HSV at the time of delivery occurs more frequently. The risk of transmitting HSV to an infant during delivery is determined in part by the mother's previous immunity to HSV. Women with primary genital HSV infections who are shedding HSV at delivery are 10 to 30 times more likely to transmit the virus to their newborn infants than are women with recurrent HSV infection who are shedding virus at delivery. With the availability of commercial serological tests that reliably can distinguish type-specific HSV antibodies, it is now possible to determine the type of maternal infection and, thus, further refine management of infants delivered to women who have active genital HSV lesions. The management algorithm presented herein uses both serological and virological studies to determine the risk of HSV transmission to the neonate who is delivered to a mother with active herpetic genital lesions and tailors management accordingly. The algorithm does not address the approach to asymptomatic neonates delivered to women with a history of genital herpes but no active lesions at delivery.

A Major Advance in Elucidating the Biology/Pathobiology of Chlamydia trachomatis

Theseveralchlamydialspecieshavebeenrecognizedfordecades as bacterial pathogens of major importance to humans and domestic animals. Chlamydia trachomatis was first identified as the etiologic agent in blinding trachoma in Africa and the Middle East and later was demonstrated to be a genital pathogen of widespreadoccurrenceinbothdevelopedandunderdevelopedareasof theworld.Indeed,thisorganismisnowconsideredtobethemost common sexually transmitted bacterial pathogen in the United States, with more than a million new such infections reported annually to the Centers for Disease Control and Prevention (1). Significantly, primary genital infection with this organism often engendersseveresequelae,includingfertilityproblemsinwomen, arthritis in both genders, and others (2, 3). Current data indicate that these sequelae involve organisms in an unusual state designated persistence, in which metabolic and genetic activity are modified to yield a largely antimicrobial-refractory organism (3, 4).

Vaginal chlamydial clearance following primary or secondary infection in mice occurs independently of TNF-α

The role of TNF-α in chlamydial clearance is uncertain. Antibody-mediated depletion of TNF-α in mice and guinea pigs has been shown not to significantly affect chlamydial clearance, whereas production of TNF-α in addition to IFN-γ from T cells has been shown to correlate with enhanced clearance. The aim of our study is to evaluate the mechanistic role of TNF-α in clearance of primary and secondary chlamydial infection from the genital tract (GT) using C57BL/6 TNF-α deficient (TNF-α−/−) and wild type (WT) mice. Chlamydial shedding from the lower GT was evaluated following primary and secondary intravaginal challenge. Also, antibody and antigen specific cytokine responses were analyzed from the infected GT and spleens, and oviduct pathology determined to analyze the role of TNF-α in upper GT pathological sequelae. MHC II−/− mice, known to display muted adaptive immune responses and failure to resolve genital chlamydial infections, were used as a negative control. Following both primary and secondary genital chlamydial infection, TNF-α−/− mice exhibited elevated granzyme B production, but similar IFN-γ and antibody responses. Importantly, absence of TNF-α did not significantly alter the resolution of infection. However, TNF-α−/− mice displayed significantly reduced upper genital tract (UGT) pathology compared to WT mice. This study demonstrates mechanistically that optimal chlamydial clearance following primary and secondary chlamydial genital infection can occur in the complete absence of TNF-α, and considered with the reduction of upper GT pathology in TNF-α−/− mice, suggests that targeted induction of anti-chlamydial TNF-α responses by vaccination may be unnecessary, and moreover could be potentially pathogenic.

PmpG 303-311 , a Protective Vaccine Epitope That Elicits Persistent Cellular Immune Responses in Chlamydia muridarum-Immune Mice

Urogenital Chlamydia serovars replicating in reproductive epithelium pose a unique challenge to host immunity and vaccine development. Previous studies have shown that CD4 T cells are necessary and sufficient to clear primary Chlamydia muridarum genital tract infections in the mouse model, making a protective CD4 T cell response a logical endpoint for vaccine development. Our previous proteomics studies identified 13 candidate Chlamydia proteins for subunit vaccines. Of those, PmpG-1 is the most promising vaccine candidate. To further that work, we derived a PmpG(303-311)-specific multifunctional Th1 T cell clone, designated PmpG1.1, from an immune C57BL/6 mouse and used it to investigate the presentation of the PmpG(303-311) epitope by infected epithelial cells. Epithelial presentation of the PmpG(303-311) epitope required bacterial replication, occurred 15 to 18 h postinfection, and was unaffected by gamma interferon (IFN-γ) pretreatment. Unlike epitopes recognized by other Chlamydia-specific CD4 T cell clones, the PmpG(303-311) epitope persisted on splenic antigen-presenting cells (APC) of mice that cleared primary genital tract infections. PmpG1.1 was activated by unmanipulated irradiated splenocytes from immune mice without addition of exogenous Chlamydia antigen, and remarkably, activation of PmpG1.1 by unmanipulated immune splenocytes was stronger 6 months postinfection than it was 3 weeks postinfection. Enhanced presentation of PmpG(303-311) epitope on splenic APC 6 months postinfection reflects some type of "consolidation" of a protective immune response. Understanding the antigen-presenting cell populations responsible for presenting PmpG(303-311) early (3 weeks) and late (6 months) postinfection will likely provide important insights into stable protective immunity against Chlamydia infections of the genital tract.

O3-S5.02 Frequent breakthrough genital HSV-2 shedding on standard and high dose valacyclovir

BackgroundShort, rapidly cleared, subclinical shedding episodes are the predominant form of HSV-2 reactivation in the genital tract. Valacyclovir 500 mg once daily (SD-VAL) reduces the risk of sexual transmission of...

Herpes Simplex and HIV Infections and Preterm PROM

Maternal human immunodeficiency virus (HIV) and genital herpes simplex virus (HSV) infection in pregnancy have potential for vertical transmission that may result in death or morbidity. The risk increases with preterm delivery and prolonged ruptured membranes. When managing preterm premature rupture of membranes, the risk of transmission must be weighed against the risk of prematurity. Before 32 to 34 weeks, expectant management is preferred for patients with well controlled HIV or recurrent active genital HSV infection. For patients with advanced HIV disease or primary genital HSV infection, the risk of vertical transmission is higher and many clinical factors need to be considered.

HSV Neutralization by the Microbicidal Candidate C5A

Genital herpes is a major risk factor in acquiring human immunodeficiency virus type-1 (HIV-1) infection and is caused by both Herpes Simplex virus type 1 (HSV-1) and HSV-2. The amphipathic peptide C5A, derived from the non-structural hepatitis C virus (HCV) protein 5A, was shown to prevent HIV-1 infection but neither influenza nor vesicular stomatitis virus infections. Here we investigated the antiviral function of C5A on HSV infections. C5A efficiently inhibited both HSV-1 and HSV-2 infection in epithelial cells in vitro as well as in an ex vivo epidermal infection model. C5A destabilized the integrity of the viral HSV membrane. Furthermore, drug resistant HSV strains were inhibited by this peptide. Notably, C5A-mediated neutralization of HSV-1 prevented HIV-1 transmission. An in vitro HIV-1 transmigration assay was developed using primary genital epithelial cells and HSV infection increased HIV-1 transmigration. Treatment with C5A abolished HIV-1 transmigration by preventing HSV infection and by preserving the integrity of the genital epithelium that was severely compromised by HSV infection. In conclusion, this study demonstrates that C5A represents a multipurpose microbicide candidate, which neutralizes both HIV-1 and HSV, and which may interfere with HIV-1 transmission through the genital epithelium.