Thomas L. Cherpes

Association between Acquisition of Herpes Simplex Virus Type 2 in Women and Bacterial Vaginosis

A longitudinal cohort study of sexually active women 18-30 years of age was conducted to identify variables associated with the acquisition of herpes simplex virus type 2 (HSV-2) infections. Six hundred seventy HSV-2-seronegative women were followed up at 4-month intervals for 1 year; acquisition of HSV-2 antibodies was detected in 32 of these women. Black race, < or =12 years of education, having a new sex partner, and bacterial vaginosis (BV) were associated with HSV-2 seroconversion on univariate analysis. Antecedent HSV-1 infection was not protective against HSV-2 acquisition. After controlling for other identified risk factors in multivariable models, the diagnosis of BV remained associated with an increased risk of acquiring HSV-2 infection (hazard ratio, 2.1; 95% confidence interval, 1.0-4.5; P=.05). In this study, the population attributable risk of BV for HSV-2 seroconversion was 21%. Additional studies are needed to determine whether screening and treatment of BV could reduce susceptibility to the acquisition of HSV-2 in women.

A Delicate Balance : Risk Factors for Acquisition of Bacterial Vaginosis Include Sexual Activity, Absence of Hydrogen Peroxide-Producing Lactobacilli, Black Race, and Positive Herpes Simplex Virus Type 2 Serology

Background: The etiology of bacterial vaginosis (BV) is poorly understood, but better definition of the risk factors associated with its acquisition should improve our understanding of this complex disease entity. Methods: A longitudinal cohort study of young sexually active women was conducted to identify variables associated with BV acquisition. Seven hundred seventy-three women without BV at enrollment were followed at 4-month intervals for 1 year. At each visit, demographic and behavioral interview data, a vaginal smear for the Gram stain diagnosis of BV, and a serum sample for detection of herpes simplex virus type 1 (HSV-1) and HSV-2 type-specific antibodies were collected. Results: The overall incidence of BV acquisition was 36 cases/100 woman-years (223 acquisitions of BV during 619 woman-years of follow-up). Acquisition of BV was independently associated with black race, cigarette smoking, vaginal intercourse, receptive anal sex before vaginal intercourse, sex with an uncircumcised male partner, lack of vaginal H2O2-producing lactobacilli, and the detection of HSV-2 serum antibodies at the visit before BV acquisition. Longitudinal analyses revealed that HSV-2 serum antibodies were independently associated with loss of H2O2-producing lactobacilli. Conclusions: Our findings suggest that multiple and diverse risk factors can contribute to BV acquisition. They also illustrate why a more complete understanding of BV pathogenesis and the formulation of effective BV prevention strategies have been elusive. Further work will be needed to determine the specific effects of HSV-2 infection on vaginal flora composition and the acquisition of BV.

Risk factors for infection with Herpes simplex virus type 2: Role of smoking, douching, uncircumcised males, and vaginal flora

Background Herpes simplex virus type 2 (HSV-2), the primary cause of genital herpes, is one of the most prevalent sexually transmitted diseases worldwide. Epidemiologic serosurveys suggest that infections occur more frequently in women than in men. Goal The goal of the study was to identify unique correlates of HSV-2 infection in women that might contribute to their increased susceptibility of infection or suggest opportunities for decreasing the incidence of disease. Study Design We enrolled 1207 women aged 18 to 30 years from three Pittsburgh health clinics in a cross-sectional study. Each woman provided demographic and behavioral information, vaginal swab specimens for bacterial culture, a vaginal smear for Gram stain diagnosis of bacterial vaginosis, and blood for HSV-1 and HSV-2 serology. Results Black race, older age, cigarette smoking, douching, a greater number of lifetime sex partners, a history of intercourse with an uncircumcised partner, the presence of vaginal group B Streptococcus, and abnormal vaginal flora were among the independent predictors of HSV-2 infection. Conclusion HSV-2 infection may be occur more often in women who douche, smoke, have sex with uncircumcised partners, or have bacterial vaginosis; these represent alterable risk factors.

Genital Tract Shedding of Herpes Simplex Virus Type 2 in Women: Effects of Hormonal Contraception, Bacterial Vaginosis, and Vaginal Group B Streptococcus Colonization

BACKGROUND Genital infections due to herpes simplex virus type 2 (HSV-2) are characterized by frequent reactivation and shedding of the virus and by the attendant risk of transmission to sexual partners. We investigated the effects of vaginal coinfections and hormonal contraceptive use on genital tract shedding of HSV-2 in women. METHODS A total of 330 HSV-2-seropositive women were followed every 4 months for a year. At each visit, one vaginal swab specimen was obtained for detection of HSV-2 by polymerase chain reaction, a second vaginal swab specimen was obtained for detection of group B Streptococcus (GBS) organisms and yeast by culture, and a vaginal smear was obtained for the diagnosis of bacterial vaginosis by Gram staining. RESULTS HSV-2 DNA was detected in 88 (9%) of 956 vaginal swab specimens. Independent predictors of genital tract shedding of HSV-2 were HSV-2 seroconversion during the previous 4 months (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.3-6.8), bacterial vaginosis (aOR, 2.3; 95% CI, 1.3-4.0), high-density vaginal GBS colonization (aOR, 2.2; 95% CI, 1.3-3.8), and use of hormonal contraceptives (aOR, 1.8; 95% CI, 1.1-2.8). CONCLUSIONS The present study identifies hormonal contraceptive use, bacterial vaginosis, and high-density vaginal GBS colonization as risk factors for genital tract shedding of HSV-2 in women. Because hormonal contraceptives are used by millions of women worldwide and because bacterial vaginosis and vaginal GBS colonization are common vaginal conditions, even modest associations with HSV-2 shedding would result in substantial attributable risks for transmission of the virus.

The Associations Between Pelvic Inflammatory Disease, Trichomonas vaginalis Infection, and Positive Herpes Simplex Virus Type 2 Serology

Objective: Roles for Chlamydia trachomatis and Neisseria gonorrhoeae infections in pelvic inflammatory disease pathogenesis are well delineated; however, the etiologic contributions of herpes simplex virus type 2 (HSV-2) and Trichomonas vaginalis have been underexplored. Goal: The goal of this study was to investigate the association between acute and plasma cell endometritis, fallopian tube obstruction, HSV-2 serology, and T. vaginalis infection. Study Design: The authors conducted a cross-sectional secondary analysis of 736 women at risk for bacterial sexually transmitted diseases that used endometrial biopsy data obtained at enrollment as well as hysterosalpingography results obtained 12 weeks after enrollment. Results: Women diagnosed with T. vaginalis at enrollment were more likely to have histologic evidence of acute endometritis. Both plasma cell and acute endometritis were significantly more common among women with positive serology HSV-2; furthermore, women coinfected with HSV-2 and C. trachomatis, N. gonorrhoeae, T. vaginalis, or bacterial vaginosis were much more likely to be diagnosed with acute endometritis than were women infected with HSV-2 or one of these pathogens alone. Among women with available HSV-2 serology and hysterosalpingogram results, HSV-2 was the only genital tract pathogen infection associated with fallopian tube obstruction. Conclusions: Our analyses demonstrate that T. vaginalis infection and positive HSV-2 serology are associated with endometritis. Further work will be needed to determine the specific roles these pathogens may play in pelvic inflammatory disease pathogenesis.

A triple entente: Virus, neurons, and CD8+ T cells maintain HSV-1 latency

Herpes simplex virus type 1 (HSV-1) travels by retrograde transport to sensory ganglia where latency is established. Recurrent disease results from virus reactivation and anterograde transport to nerve termini. Prevention of reactivation requires a complex interplay among virus, neuron, and immune response. Study of this tripartite relationship suggests possible interaction, and even communication among these components, that direct an immune response that allows for control of virus while preserving the viability of host tissue. Exciting new evidence supports the view that CD8+ effector T cells employ both lytic granule-dependent and interferon gamma-dependent effector mechanisms in maintaining HSV-1 latency.

Early CD4+ T Cell Help Prevents Partial CD8+ T Cell Exhaustion and Promotes Maintenance of Herpes Simplex Virus 1 Latency

HSV-specific CD8+ T cells provide constant immunosurveillance of HSV-1 latently infected neurons in sensory ganglia, and their functional properties are influenced by the presence of latent virus. In this study, we show that ganglionic HSV-specific CD8+ T cells exhibit a higher functional avidity (ability to respond to low epitope density) than their counterparts in noninfected lungs, satisfying a need for memory effector cells that can respond to low densities of viral epitopes on latently infected neurons. We further show that lack of CD4+ T cell help during priming leads to a transient inability to control latent virus, which was associated with a PD-1/PD-L1 mediated reduced functional avidity of ganglionic HSV-specific CD8+ T cells. CD4+ T cells are not needed to maintain CD8+ T cell memory through 34 d after infection, nor do they have a direct involvement in the maintenance of HSV-1 latency.

Comparative Genomic Analyses of 17 Clinical Isolates of Gardnerella vaginalis Provide Evidence of Multiple Genetically Isolated Clades Consistent with Subspeciation into Genovars

Gardnerella vaginalis is associated with a spectrum of clinical conditions, suggesting high degrees of genetic heterogeneity among stains. Seventeen G. vaginalis isolates were subjected to a battery of comparative genomic analyses to determine their level of relatedness. For each measure, the degree of difference among the G. vaginalis strains was the highest observed among 23 pathogenic bacterial species for which at least eight genomes are available. Genome sizes ranged from 1.491 to 1.716 Mb; GC contents ranged from 41.18% to 43.40%; and the core genome, consisting of only 746 genes, makes up only 51.6% of each strains genome on average and accounts for only 27% of the species supragenome. Neighbor-grouping analyses, using both distributed gene possession data and core gene allelic data, each identified two major sets of strains, each of which is composed of two groups. Each of the four groups has its own characteristic genome size, GC ratio, and greatly expanded core gene content, making the genomic diversity of each group within the range for other bacterial species. To test whether these 4 groups corresponded to genetically isolated clades, we inferred the phylogeny of each distributed gene that was present in at least two strains and absent in at least two strains; this analysis identified frequent homologous recombination within groups but not between groups or sets. G. vaginalis appears to include four nonrecombining groups/clades of organisms with distinct gene pools and genomic properties, which may confer distinct ecological properties. Consequently, it may be appropriate to treat these four groups as separate species.

Reevaluating the CD8 T-Cell Response to Herpes Simplex Virus Type 1: Involvement of CD8 T Cells Reactive to Subdominant Epitopes

ABSTRACT In C57BL/6 (B6) mice, most herpes simplex virus (HSV)-specific CD8 T cells recognize a strongly immunodominant epitope on glycoprotein B (gB498) and can inhibit HSV type 1 (HSV-1) reactivation from latency in trigeminal ganglia (TG). However, half of the CD8 T cells retained in latently infected TG of B6 mice are not gB498 specific and have been largely ignored. The following observations from our current study indicate that these gB498-nonspecific CD8 T cells are HSV specific and may contribute to the control of HSV-1 latency. First, following corneal infection, OVA257-specific OT-1 CD8 T cells do not infiltrate the infected TG unless mice are simultaneously immunized with OVA257 peptide, and then they are not retained. Second, 30% of CD8 T cells in acutely infected TG that produce gamma interferon in response to HSV-1 stimulation directly ex vivo are gB498 nonspecific, and these cells maintain an activation phenotype during viral latency. Finally, gB498-nonspecific CD8 T cells are expanded in ex vivo cultures of latently infected TG and inhibit HSV-1 reactivation from latency in the absence of gB498-specific CD8 T cells. We conclude that many of the CD8 T cells that infiltrate and are retained in infected TG are HSV specific and potentially contribute to maintenance of HSV-1 latency. Identification of the viral proteins recognized by these cells will contribute to a better understanding of the dynamics of HSV-1 latency.

Cunnilingus and Vaginal Intercourse Are Risk Factors for Herpes Simplex Virus Type 1 Acquisition in Women

Objective: Although numerous cross-sectional studies have identified herpes simplex virus type 1 (HSV-1) as an important genital pathogen, the specific sexual activities associated with HSV-1 infection are not well delineated. Our objective was to identify demographic and behavioral variables in women associated with the prevalence and acquisition of HSV-1. Study: From 1998 through 2000, we enrolled 1207 nonpregnant 18- to 30-year-old women from 3 Pittsburgh, Pennsylvania, area health clinics in a prospective cohort study. Serum from the women was tested each visit for the presence of type-specific HSV-1 antibodies. Results: At enrollment, HSV-1 serum antibodies were detected in only 38% of women ≤20 years of age. Black race, ≤12 years education, older age, and a history of at least 5 lifetime male sex partners were independently associated with the prevalence of HSV-1. In longitudinal analyses, women who had vaginal intercourse were more likely than sexually inactive women to acquire HSV-1 (6.8 vs. 1.2 cases per 100 woman-years of follow up; P = 0.05). Similarly, women who only had receptive oral sex, without vaginal intercourse, were also more likely than sexually inactive women to acquire HSV-1 (9.8 vs. 1.2 cases per 100 woman-years of follow up; P = 0.04). Conclusions: Receiving cunnilingus and vaginal intercourse are important risk factors for the acquisition of HSV-1 among young women. Genital herpes prevention strategies will need to consider both the increased susceptibility for HSV-1 acquisition that young adults now have at sexual debut and the important contributions of HSV-1 to the burgeoning genital herpes epidemic.