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Highly-Exposed HIV-1 seronegative Female Commercial Sex Workers sustain in their genital mucosa increased frequencies of tolerogenic myeloid and regulatory T-cells.

ABSTRACT: We and others have shown that HIV-1 highly-exposed seronegative (HESN) female commercial sex workers (CSWs) maintain low genital inflammatory conditions to prevent HIV infection. HIV-1 interacts with toll-like receptors (TLR)-7/8 to induce interferon (IFN)-?, an important antiviral and immunomodulatory cytokine, which act together with interleukin (IL)-10, human leukocyte antigen (HLA)-G and immunoglobulin-like transcript (ILT)-4 to initiate a "tolerogenic/regulatory" anti-inflammatory loop. In view of further unravelling elements associated with natural immunity to HIV-1, we have characterised TLR-7, IFN-?, IL-10, HLA-G and ILT-4 expression profiles in the genital tract of female CSWs and HIV-1-uninfected non-CSWs from Benin. Endocervical myeloid HLA-DR⁺ cells from HESN CSWs expressed higher levels of IFN-?, TLR-7, IL-10 and HLA-G than those from both HIV-1-infected CSWs and HIV-1-uninfected non-CSWs. Further characterization of the endocervical myeloid HLA-DR⁺ cells in HESN CSWs revealed a population of "tolerogenic" CD103⁺ CD14⁺ CD11c⁺ myeloid cells expressing high levels of IFN-? and IL-10. Concomitantly, HESN CSWs had higher frequencies of endocervical regulatory CD4⁺ T-cells when compared to those from the two other groups of women. These novel findings provide strong evidence to support the implication of tolerogenic myeloid cells expressing high levels of antiviral molecules in shaping the genital mucosal immune response to prevent HIV infection.

SUBMITTER: Thibodeau V

PROVIDER: S-EPMC5338327 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Highly-Exposed HIV-1 seronegative Female Commercial Sex Workers sustain in their genital mucosa increased frequencies of tolerogenic myeloid and regulatory T-cells.

Thibodeau V V Fourcade L L Labbé A-C AC Alary M M Guédou F F Poudrier J J Roger M M

Scientific reports 20170306

We and others have shown that HIV-1 highly-exposed seronegative (HESN) female commercial sex workers (CSWs) maintain low genital inflammatory conditions to prevent HIV infection. HIV-1 interacts with toll-like receptors (TLR)-7/8 to induce interferon (IFN)-α, an important antiviral and immunomodulatory cytokine, which act together with interleukin (IL)-10, human leukocyte antigen (HLA)-G and immunoglobulin-like transcript (ILT)-4 to initiate a "tolerogenic/regulatory" anti-inflammatory loop. In ...[more]

PMID: 28262752

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Project description:Although nonhuman primate studies have shown that simian immunodeficiency virus/simian-human immunodeficiency virus (SIV/SHIV) exposure during preexposure prophylaxis (PrEP) with oral tenofovir can induce SIV immunity without productive infection, this has not been documented in humans. We evaluated cervicovaginal IgA in Partners PrEP Study participants using a subtype C primary isolate and found that women on PrEP had IgA with higher average human immunodeficiency virus type 1 (HIV-1)-neutralizing magnitude than women on placebo (33% versus 7%; P = 0.008). Using a cutoff of ?90% HIV-1 neutralization, 19% of women on-PrEP had HIV-1-neutralizing IgA compared to 0% of women on placebo (P = 0.09). We also estimated HIV-1 exposure and found that the proportion of women with HIV-1-neutralizing IgA was associated with the level of HIV-1 exposure (P = 0.04). Taken together, our data suggest that PrEP and high levels of exposure to HIV may each enhance mucosal HIV-1-specific humoral immune responses in sexually exposed but HIV-1-uninfected individuals. IMPORTANCE:Although there is not yet an effective HIV-1 vaccine, PrEP for at-risk HIV-1-uninfected individuals is a highly efficacious intervention to prevent HIV-1 acquisition and is currently being recommended by the CDC and WHO for all individuals at high risk of HIV-1 acquisition. We previously demonstrated that PrEP use does not enhance peripheral blood HIV-1-specific T-cell responses in HIV-exposed individuals. Here, we evaluate for cervicovaginal HIV-neutralizing IgA responses in genital mucosal secretions of HIV-exposed women, which is likely a more relevant site than peripheral blood for observation of potentially protective immune events occurring in response to sexual HIV-1 exposure for various periods. Furthermore, we assess for host response in the context of longitudinal quantification of HIV-1 exposure. We report that HIV-neutralizing IgA is significantly correlated with higher HIV-1 exposure and, furthermore, that there are more women with HIV-1-neutralizing IgA in the on-PrEP group than in the placebo group.

Project description:BackgroundAlthough female sex workers (FSWs) report high levels of condom use with commercial sex clients, particularly after targeted HIV preventive interventions have been implemented, condom use is often low with non-commercial partners. There is limited understanding regarding the factors that influence condom use with FSWs' non-commercial partners, and of how programs can be designed to increase condom use with these partners. The main objectives of this study were therefore to describe FSWs' self-reported non-commercial partners, along with interpersonal factors characterizing their non-commercial partnerships, and to examine the factors associated with consistent condom use (CCU) within non-commercial partnerships.MethodsThis study used data collected from cross-sectional questionnaires administered to 988 FSWs in four districts in Karnataka state in 2006-07. We used bivariate and multivariable logistic regression analysis to examine the relationship between CCU (i.e., 'always' compared to 'never', 'sometimes' or 'frequently') with non-commercial partners of FSWs (including the respondents' husband or main cohabiting partner [if not married] and their most recent non-paying partner [who is neither a husband nor the main cohabiting partner, and with whom the FSW had sex within the previous year]) and interpersonal factors describing these partnerships, as well as social and environmental factors. Weighting and survey methods were used to account for the cluster sampling design.ResultsOverall, 511 (51.8%) FSWs reported having a husband or cohabiting partner and 247 (23.7%) reported having a non-paying partner. CCU with these partners was low (22.6% and 40.3% respectively). In multivariable analysis, the odds of CCU with FSWs' husband or cohabiting partner were 1.8-fold higher for FSWs whose partner knew she was a sex worker (adjusted odds ratio [AOR]: 1.84, 95% confidence intervals[CI]: 1.02-3.32) and almost 6-fold higher if the FSW was unmarried (AOR: 5.73, 95%CI: 2.79-11.76]. CCU with FSWs' non-paying partner decreased by 18% for each one-year increase in the duration of the relationship (AOR: 0.82, 95%CI: 0.68-0.97).ConclusionsThis study revealed important patterns and interpersonal determinants of condom use within non-commercial partnerships of FSWs. Integrated structural and community-driven HIV/STI prevention programs that focus on gender and reduce sex work stigma should be investigated to increase condom use in non-commercial partnerships.

Project description:ObjectiveCationic proteins found in cervicovaginal secretions (CVS) are known to contribute to the early antiviral immune response against HIV-infection in vitro. We here aimed to define additional antiviral factors that are over-expressed in CVS from female sex workers at high risk of infection.MethodsCVS were collected from Kenyan HIV-seronegative (n = 34) and HIV-seropositive (n = 12) female sex workers, and were compared with those from HIV-seronegative low-risk women (n = 12). The highly exposed seronegative (HESN) sex workers were further divided into those with less (n = 22) or more (n = 12) than three years of documented sex work. Cationic protein-depleted CVS were assessed for HIV-neutralizing activity by a PBMC-based HIV-neutralizing assay, and then characterized by proteomics.ResultsHIV neutralizing activity was detected in all unprocessed CVS, however only CVS from the female sex worker groups maintained its HIV neutralizing activity after cationic protein-depletion. Differentially abundant proteins were identified in the cationic protein-depleted secretions including 26, 42, and 11 in the HESN>3 yr, HESN<3 yr, and HIV-positive groups, respectively. Gene ontology placed these proteins into functional categories including proteolysis, oxidation-reduction, and epidermal development. The proteins identified in this study include proteins previously associated with the HESN phenotype in other cohorts as well as novel proteins not yet associated with anti-HIV activities.ConclusionWhile cationic proteins appear to contribute to the majority of the intrinsic HIV neutralizing activity in the CVS of low-risk women, a broader range of non-cationic proteins were associated with HIV neutralizing activity in HESN and HIV-positive female sex workers. These results indicate that novel protein factors found in CVS of women with high-risk sexual practices may have inherent antiviral activity, or are involved in other aspects of anti-HIV host defense, and warrant further exploration into their mode of action.

Dataset Information

Highly-Exposed HIV-1 seronegative Female Commercial Sex Workers sustain in their genital mucosa increased frequencies of tolerogenic myeloid and regulatory T-cells.

Publications

Highly-Exposed HIV-1 seronegative Female Commercial Sex Workers sustain in their genital mucosa increased frequencies of tolerogenic myeloid and regulatory T-cells.

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