Mechanisms of type I IFN signaling and HIV risk in the female genital tract

Centre/Aids Programme/Res/South Africa, Durban

Investigators

Abstract

ABSTRACT Previously, we carried out large-scale analysis of mucosal cytokines and HIV acquisition in high-risk women from KwaZulu-Natal, South Africa, enrolled as part of the CAPRISA 004 TFV 1% gel study (n = 774). Using a prospective cohort design, we validated our previous finding that inflammatory cytokines increase the risk of HIV acquisition. Of the cytokines associated with increased risk, one of the strongest associations was observed for the key type I IFN, IFN2 (p = 10E-6). Women in upper quartile for IFN2 were at 4-fold greater risk of acquiring HIV, compared to women in the lowest quartile (HR 3.9, 95% CI 1.7-9.1). On the surface this seems counter- intuitive, as type I IFN have strong anti-HIV effects both in vitro and when given in vivo as a therapeutic or prophylactic in non-human primate model. To reconcile these observations, we hypothesize that chronic type I IFN upregulation in the female reproductive tract (FRT) leads to dysregulation of IFN signaling, resulting in downregulation of antiviral genes, increase in generalized inflammation and increase in susceptibility of target cells at the site of infection. This hypothesis would provide an explanation as to why a classical anti- viral program that should be protective actually leads to higher rates of HIV acquisition. Utilizing samples from the ongoing CAPRISA 018 tenofovir alafenamide (TAF) sub-dermal implant trial, we will determine whether prolonged IFN2 upregulation in the FRT leads to decreased IFN responsiveness and IFN-stimulated gene (ISG) expression in genital immune cells. Next, we will formally test if the chronic increase in IFN2 expression and ISG downregulation correspond to breakthrough HIV infections in young women enrolled in CAPRISA 018. Finally, we will use an in vitro PBMC model to determine the mechanism by which prolonged IFN upregulation leads to ISG downregulation and subsequent increase in HIV risk.