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We recently reported that the risk of sexually acquired HIV-1 infection is increased significantly by variants in the gene encoding CD101, a protein thought to modify inflammatory responses. Using blood samples from individuals with and without these variants, we demonstrate that CD101 variants modify the prevalence of circulating inflammatory cell types and show that CD101 variants are associated with increased proinflammatory cytokine production by circulating T cells. One category of CD101 variants is associated with a reduced capacity of regulatory T cells to suppress T cell cytokine production, resulting in a reduction in the baseline level of immune quiescence. These data are supported by transcriptomics data revealing alterations in the intrinsic regulation of antiviral pathways and HIV resistance genes in individuals with CD101 variants. Our data support the hypothesis that CD101 contributes to homeostatic regulation of bystander inflammation, with CD101 variants altering heterosexual HIV-1 acquisition by facilitating increased prevalence and altered function of T cell subsets.

BackgroundDaily oral tenofovir-based pre-exposure prophylaxis (PrEP) is high efficacious for HIV prevention among women with high adherence. However, the effect of abnormal vaginal microbiota on PrEP efficacy is of concern. We investigated whether bacterial vaginosis modified the efficacy of oral PrEP.MethodsWe used prospectively collected data from women in the Partners PrEP Study, a placebo-controlled trial of daily oral PrEP (either tenofovir monotherapy or a combination of tenofovir and emtricitabine) in HIV serodiscordant couples aged 18 years or older in Kenya and Uganda that showed high efficacy in women. We used Cox proportional hazards regression to assess PrEP efficacy among subgroups of women defined by bacterial vaginosis status based on yearly microscopy and Nugent scoring (0-3 indicated healthy microbiota, 4-6 intermediate, and 7-10 bacterial vaginosis). In separate efficacy analyses, we also investigated individual components of the score (ie, detection of Gardnerella vaginalis or Bacteroides spp and non-detection of Lactobacillus spp) as markers of abnormal microbiota.FindingsOf 1470 women (median age 33 years), 357 (24%) had bacterial vaginosis at enrolment. 45 women seroconverted to HIV. The HIV prevention efficacy of PrEP did not differ significantly among women with healthy microbiota (incidence 0·6 per 100 person years in PrEP group and 2·5 per 100 person-years in the placebo group; efficacy 76·55% [95% CI 43·09 to 90·37]), intermediate microbiota (HIV incidence 1·8 per 100 person-years in the PrEP group and 3·5 per 100 person-years in the placebo group; efficacy 62·72% [95% CI -66·59 to 91·66]), or bacterial vaginosis (HIV incidence 0·9 per 100 person-years in the PrEP group and 3·5 per 100 person-years in the placebo group; efficacy 72·50% [95% CI 5·98 to 91·95]; pinteraction=0·871). PrEP efficacy was not significantly different between women with detected G vaginalis or Bacteroides spp morphotypes and those without these morphotypes (efficacy 68·62% vs 76·72%; pinteraction=0·652); or between those with Lactobacillus spp morphotypes and those without (70·48% vs 74·08%; pinteraction=0·86).InterpretationAmong African women with a high prevalence of bacterial vaginosis and high adherence to PrEP, the efficacy of daily oral PrEP for HIV prevention did not differ significantly among women with abnormal versus healthy vaginal microbiota as defined by Nugent score. These data are reassuring that oral PrEP delivery to women can continue without the need for concurrent testing for bacterial vaginosis or vaginal dysbiosis.FundingBill & Melinda Gates Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Institute of Allergy and Infectious Diseases.

BackgroundImmune reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV)-infected persons beginning antiretroviral therapy (ART) has been incompletely characterized for herpes simplex virus type 2 (HSV-2).MethodsWe evaluated genital ulcer disease (GUD) and HSV-2-associated GUD at quarterly visits or when spontaneously reported at monthly visits in 3381 HIV/HSV-2-coinfected individuals in a placebo-controlled trial of suppressive acyclovir therapy to prevent HIV transmission, 349 of whom initiated ART during the study. Incidence was calculated for months before and after ART initiation, and incidence rate ratios (IRRs) were calculated.ResultsGUD incidence increased from 15.0 episodes per 100 person-years before ART to 26.9 episodes per 100 person-years in the first full quarter after ART initiation (IRR, 1.83;P= .03), and the incidence of HSV-2-associated GUD increased from 8.1 to 19.0 episodes per 100 person-years (IRR, 2.20;P= .02). Subsequently, the incidence of GUD was similar to that before ART, although the numbers were small. Persons receiving suppressive acyclovir had fewer GUD episodes, but the IRR after beginning ART was similar in the acyclovir and placebo groups.ConclusionsInitiation of ART in HIV/HSV-2-coinfected persons is associated with a transient increase in GUD and HSV-2 GUD. Acyclovir reduces the incidence of GUD but does not prevent an increase in GUD incidence during the first quarter following initiation of ART.

BackgroundThe efficacy of condoms for protection against transmission of herpes simplex virus type 2 (HSV-2) has been examined in a variety of populations with different effect measures. Often the efficacy has been assessed as change in hazard of transmission with consistent vs inconsistent use, independent of the number of acts. Condom efficacy has not previously measured on a per-act basis.MethodsWe examined the per-act HSV-2 transmission rates with and without condom use among 911 African HSV-2 and human immunodeficiency virus type 1 (HIV-1) serodiscordant couples followed for an average of 18 months in an HIV prevention study. Infectivity models were used to associate the log10 probability of HSV-2 transmission over monthly risk periods with reported numbers of protected and unprotected sex acts. Condom efficacy was computed as the proportionate reduction in transmission risk for protected relative to unprotected sex acts.ResultsTransmission of HSV-2 occurred in 68 couples, including 17 with susceptible women and 51 with susceptible men. The highest rate of transmission was from men to women: 28.5 transmissions per 1000 unprotected sex acts. We found that condoms were differentially protective against HSV-2 transmission by sex; condom use reduced per-act risk of transmission from men to women by 96% (P < .001) and marginally from women to men by 65% (P = .060).ConclusionsCondoms are recommended as an effective preventive method for heterosexual transmission of HSV-2.

BackgroundAntiretroviral preexposure prophylaxis (PrEP), using daily oral combination tenofovir disoproxil fumarate plus emtricitabine, is an effective human immunodeficiency virus (HIV) prevention strategy for populations at high risk of HIV acquisition. Although the primary mode of action for the protective effect of PrEP is probably direct antiviral activity, nonhuman primate studies suggest that PrEP may also allow for development of HIV-specific immune responses, hypothesized to result from aborted HIV infections providing a source of immunologic priming. We sought to evaluate whether PrEP affects the development of HIV-specific immune response in humans.Methods and resultsWithin a PrEP clinical trial among high-risk heterosexual African men and women, we detected HIV-specific CD4(+) and CD8(+) peripheral blood T-cell responses in 10%-20% of 247 subjects evaluated. The response rate and magnitude of T-cell responses did not vary significantly between those assigned PrEP versus placebo, and no significant difference between those assigned PrEP and placebo was observed in measures of innate immune function.ConclusionsWe found no evidence to support the hypothesis that PrEP alters either the frequency or magnitude of HIV-specific immune responses in HIV-1-exposed seronegative individuals. These results suggest that PrEP is unlikely to serve as an immunologic prime to aid protection by a putative HIV vaccine.

BackgroundA heightened proinflammatory state has been hypothesized to enhance human immunodeficiency virus type 1 (HIV-1) transmission - both susceptibility of HIV-1-exposed persons and infectiousness of HIV-1-infected persons.MethodsUsing prospective data from heterosexual African couples with HIV-1 serodiscordance, we conducted a nested case-control analysis to assess the relationship between cytokine concentrations and the risk of HIV-1 acquisition. Case couples (n = 120) were initially serodiscordant couples in which HIV-1 was transmitted to the seronegative partner during the study; control couples (n = 321) were serodiscordant couples in which HIV-1 was not transmitted to the seronegative partner. Differences in a panel of 30 cytokines were measured using plasma specimens from both HIV-1-susceptible and HIV-1-infected partners. Plasma was collected before seroconversion for cases.ResultsFor both HIV-1-infected and HIV-1-susceptible partners, cases and controls had significantly different mean responses in cytokine panels (P < .001, by the Hotelling T(2) test), suggesting a broadly different pattern of immune activation for couples in which HIV-1 was transmitted, compared with couples without transmission. Individually, log10 mean concentrations of interleukin 10 (IL-10) and CXCL10 were significantly higher for both HIV-1-susceptible and HIV-1-infected case partners, compared with HIV-1-susceptible and HIV-1-infected control partners (P < .01 for all comparisons). In multivariate analysis, HIV-1 transmission was significantly associated with elevated CXCL10 concentrations in HIV-1-susceptible partners (P = .001) and with elevated IL-10 concentrations in HIV-1-infected partners (P = .02).ConclusionsImmune activation, as measured by levels of cytokine markers, particularly elevated levels of IL-10 and CXCL1, are associated with increased HIV-1 susceptibility and infectiousness.

An abstract of the article "Characteristics of HIV Discordant Couples who Separated while Enrolled in a HIV Prevention Clinical Trial in Kenya" by Lawrence Mwaniki Mwihaki, Elizabeth Mugoiri Irungu, John Njoroge Mwathi and colleagues is presented.

Introduction: cervical intraepithelial neoplasia the precursor of cervical cancer occurs with increased frequency in women infected with human immunodeficiency virus (HIV). This study aimed at determining the prevalence and correlates of abnormal cervical cytology among HIV-infected women and compare to the uninfected women. Methods: a cross-sectional study conducted among HIV-infected and uninfected women enrolled in a HIV study in Central Kenya. All women had baseline Pap smear examination assessed using Bethesda system. Bivariate and multivariate logistic regression methods were employed to assess the correlates of cervical squamous epithelial lesions (CSIL). Results: a total 480 women had an acceptable baseline smear, 373 (78%) were HIV- infected. Median age was 30.2 years [IQR 25.4- 35.5]. Overall prevalence of CSIL was 37% (176/480) with the prevalence of low grade squamous intraepithelial lesion (LSIL), atypical squamous cells undetermined significance (ASCUS), high grade squamous intraepithelial lesions (HSIL) and atypical glandular cells (AGC) were 17%, 14%, 4% and 2% respectively. HIV-infected women had a higher prevalence of CSIL at 42% as compared to HIV- uninfected women at 19%. HIV infection was the predictor associated with development of CSIL at multivariate analysis and specifically, HIV-infected women were 3 times (AOR 3.1, 95% CI: 1.8 - 5.4, p<0.005) more likely to have CSIL than HIV- uninfected women. The age 35 - 44 years was protective to developing CSIL (AOR 0.45, 95% CI: 0.24 - 0.87, p=0.018). Conclusion: cervical squamous epithelial lesions is a major problem among Kenyan women. HIV infection confers a higher risk to development of CSIL. Cervical cancer screening should be an established practice in HIV programs. [ABSTRACT FROM AUTHOR]