Higher mucosal antibody concentrations in women with genital tract inflammation

Inflammatory cytokines augment humoral responses by stimulating antibody production and inducing class-switching. In women, genital inflammation (GI) significantly modifies HIV risk. However, the impact of GI on mucosal antibodies remains undefined. We investigated the impact of GI, pre-HIV infection, on antibody isotypes and IgG subclasses in the female genital tract. Immunoglobulin (Ig) isotypes, IgG subclasses and 48 cytokines were measured prior to HIV infection in cervicovaginal lavages (CVL) from 66 HIV seroconverters (cases) and 66 matched HIV-uninfected women (controls) enrolled in the CAPRISA 004 and 008 1% tenofovir gel trials. Pre-HIV infection, cases had significantly higher genital IgM (4.13; IQR, 4.04–4.19) compared to controls (4.06; IQR, 3.90–4.20; p = 0.042). More than one-quarter of cases (27%) had GI compared to just over one-tenth (12%) in controls. Significantly higher IgG1, IgG3, IgG4 and IgM (all p < 0.05) were found in women stratified for GI compared to women without. Adjusted linear mixed models showed several pro-inflammatory, chemotactic, growth factors, and adaptive cytokines significantly correlated with higher titers of IgM, IgA and IgG subclasses (p < 0.05). The strong and significant positive correlations between mucosal antibodies and markers of GI suggest that GI may impact mucosal antibody profiles. These findings require further investigation to establish a plausible biological link between the local inflammatory milieu and its consequence on these genital antibodies.

Higher Mucosal Antibody Concentrations in Women with Genital Tract Inflammation

Inflammatory cytokines augment humoral responses by stimulating antibody production and inducing class-switching. In women, genital inflammation (GI) significantly modifies HIV risk. However, the impact of GI on mucosal antibodies remains undefined. We investigated the impact of GI, pre-HIV infection, on antibody isotypes and IgG subclasses in the female genital tract. Immunoglobulin (Ig) isotypes, IgG subclasses and 48 cytokines were measured prior to HIV infection in cervicovaginal lavages (CVL) from 66 HIV seroconverters (cases) and 66 matched HIV-uninfected women (controls) enrolled in the CAPRISA 004 and 008 tenofovir gel trials. Pre-HIV infection, cases had significantly higher genital IgM (4.13; IQR, 4.04-4.19) compared to controls (4.06; IQR, 3.90-4.20; p=0.042). More than one-quarter of cases (27%) had GI compared to just over one-tenth (12%) in controls. Significantly higher IgG1, IgG3, IgG4 and IgM (all p<0.05) were found in women stratified for GI compared to women without. Adjusted linear regression analyses showed several pro-inflammatory, chemotactic, growth factors, and adaptive cytokines significantly correlated with higher titers of IgM and IgG subclasses (p<0.05). The strong and significant positive correlations between mucosal antibodies and markers of GI suggest that GI may impact mucosal antibody profiles. These findings require further investigation to establish a plausible biological link between the local inflammatory milieu and its consequence on these genital antibodies.

Acceptability of tenofovir gel as a vaginal microbicide among women in a phase I trial a mixed-methods study,

THE GLOBAL HIV EPIDEMIC increasingly affectswomen.1 For most, the only risk factor for becominginfected is the behavior of their male sexualpartners.1 Condoms often are unacceptableand insufficiently used,2–4 gender-based powerimbalances can make them difficult to negotiate,4–7 and religious beliefs, fertility needs, fear ofimplied infidelity, and preferences for sex withouta barrier are challenges to their acceptabilityand use. Women-initiated HIV prevention methodsare urgently needed, making the developmentof vaginal microbicides that reduce the likelihoodof sexual transmission of HIV a majorpublic health priority.First-generation vaginal microbicides will mostlikely be topical gels inserted into the vagina withan applicator. A variety of microbicides is currentlyunder development, and six have enteredlate-stage clinical trials.8–12 Initial product acceptabilityhas been assessed in clinical trials,13–16 surveysof product attributes among potentialusers17,18 and their partners,19 and studies that useover-the-counter (OTC) surrogates or placebo gelwith presumed similar formulation and applicationcharacteristics as eventual products.20–23 Acceptabilityassessments in early clinical trials areespecially important because their findings can influencefurther development of the product.Here, we report on acceptability data amongwomen participating in a phase I trial of tenofovirgel, a candidate microbicide that inhibits HIV reversetranscriptase. Details of the trial are reportedelsewhere,24 as is acceptability amongmale partners of trial participants.25 This was thefirst human trial of a topical antiretroviral thatspecifically inhibits a necessary replication stepin the HIV life cycle. Interest in this approach toHIV prevention has increased in recent yearssince efficacy trials of a topical surfactant(nonoxynyl-9) and a nonspecific inhibitor of HIVbinding (cellulose sulfate) indicated that thesetwo types of compounds were not protective andpotentially increased HIV transmission in womenwho had frequent sexual exposures to HIV. Severallarger-scale, expanded safety and proof-ofconcepttrials of tenofovir gel are now underway,based in part on the safety, tolerability, and acceptabilityof this microbicide demonstrated inthe study described in this paper.

Treatment with commonly used antiretroviral drugs induces a type I/III interferon signature in the gut in the absence of HIV infection

Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are used for HIV treatment and prevention. Previously, we found that topical rectal tenofovir gel caused immunological changes in the mucosa. Here we assessed the effect of oral TDF/FTC in three HIV pre-exposure prophylaxis trials, two with gastrointestinal and one with cervicovaginal biopsies. TDF/FTC induced type I/III interferon-related (IFN I/III) genes in the gastrointestinal tract, but not blood, with strong correlations between the two independent rectal biopsy groups (Spearman r=0.91) and between the rectum and duodenum (r=0.81). Gene set testing also indicated stimulation of type I/III pathways in the ectocervix, as well as of cellular proliferation in the duodenum. mRNA sequencing, digital droplet PCR, proteomics, and immunofluorescence staining confirmed IFN I/III pathway stimulation in the gastrointestinal tract. Thus, oral TDF/FTC stimulates an IFN-I/III signature throughout the gut, which could increase antiviral efficacy but also cause chronic immune activation in HIV prevention and treatment settings.

Frequency of Hepatitis B Virus Resistance Mutations in Women Using Tenofovir Gel as Pre-Exposure Prophylaxis

Intermittent use of a single antiretroviral agent in the presence of a replicating virus could potentially increase the development of antiviral resistance. The pericoital, before-and-after sex, dosing regimen used in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 tenofovir gel trial meant that women who were infected with hepatitis B virus (HBV) were exposed intermittently to tenofovir during their participation. The impact of this dosing regimen on HBV resistance was assessed by amplification of the HBV polymerase region from 37 stored plasma samples of women who were HBV surface antigen positive. All samples belonged to HBV genotype A. None of the known tenofovir resistance mutations (M240V/I, L180M, A194T, V214A, N238T) were identified in any individuals. While it is reassuring that no resistance mutations were found among women using topical tenofovir, the rapidly expanding access to oral tenofovir-containing HIV pre-exposure prophylaxis (PrEP), with higher systemic exposure to the drug, makes monitoring for potential HBV drug resistance important.