The impact of TGF-β on the genital immune environment associated with HIV risk in young women.

Abstract

Background: The HIV pandemic has disproportionally affected young women living in sub-Saharan Africa, with most new infections transmitted via condomless sex. Semen exposure is shown to increase several cytokines, cellular and barrier-related biomarkers of inflammation associated with HIV acquisition in women. The predominance of the anti-inflammatory transforming growth factor-beta (TGF-β) cytokine is well established in semen, and regulation of the cervical immune response is meant to facilitate conception. In this study, we investigated the contribution of TGF-β to the genital inflammatory profile linked to HIV risk in women. Methods: This study included a subset of 132 CAPRISA 008 trial participants with a biannual sampling of genital specimens (N=641 visits). The presence of prostate-specific antigen (PSA) in cervicovaginal lavage (CVL) was determined by ELISA and indicated the likelihood of condomless sex and semen exposure within 48 hours of genital sampling. Multiplex ELISA assays were used to determine the concentrations of TGF-β isoforms 1, 2, 3 and 48 other cytokines in CVL specimens. Flow cytometrywas conducted to identify activated (CD38+, HLA-DR+, CCR5+ and/or Ki67+) CD4+ T cell populations among cervical mononuclear cells collected from cytobrushes. Multivariable linear mixed models assessed associations between TGF-β concentrations and semen exposure and with cellular and cytokine biomarkers of inflammation. Results: TGF-β isoform concentrations were similar in CVL specimens with and without evidence of recent semen exposure. Further, independent of semen exposure, TGF-β1 detection and TGF-β3 concentrations were associated with significant decreases in multiple FRT cytokine concentrations. TGF-β1 detection and TGF-β2 concentrations significantly reduced multiple populations of activated CD4+ T cells at the FRT. Conclusion: Although TGF-β isoforms were differentially expressed in the FRT and differed in the nature of their individual associations with local cytokine concentrations and cellular frequencies, their general relationship with reduced levels of genital cytokines and immune cells attests to their documented immunomodulatory effects. TGF-β concentrations were not associated with PSA detection, which likely indicates a normalisation of TGF-β levels in genital fluid within 48 hours after intromission. Although TGF-β concentrations were independently associated with dampening local cellular and cytokine levels, the previously observed relationship between semen exposure and increased levels of inflammatory biomarkers was maintained in the cohort. Further interrogation is required to determine the dynamics of intromitted or endogenous TGF-β and inflammatory biomarkers, the persistence of their immune impact, and the relation to HIV risk.