Deciphering the impact of sex in early subtype C HIV infection and during HART

Current estimates suggest that 17.8 million women are infected with HIV-1 and that it is the leading cause of death in women of reproductive age. However, many studies of HIV-1 transmission and pathogenesis to date have focused on a single sex and are thus unable to directly compare disease course and outcomes between men and women. The initial experiments outlined in this grant utilize samples from a cohort of subtype C HIV-1 acutely infected Zambian men and women that allow for direct comparison of viral, transcriptional and immunologic characteristics between the sexes in individuals with a common genetic background. Paradoxically, even though CD4+ T cells from acutely infected women are significantly more highly activated (CD38+) than in men, women have consistently lower viral load than men, both in the earliest stages and chronic phase of infection. On the other hand, while women exhibit similarly effective levels of viral suppression on antiretroviral treatment (HART), they do bear a greater burden of non-AIDS comorbidities than men. These observations likely result from a complex interaction between a number of viral, hormonal and immunological factors, including the increased production of type I interferons (IFN) in women which can simultaneously cause immune activation as well as restriction of viral replication. In order to understand the molecular basis of these sex-based differences, we propose three Specific Aims: Aim 1: Assess sex-specific differences in immunological and transcriptional profiles of CD4+ T cells in early infection. Aim 2: In ART-suppressed women and men, define the landscape of immune cell activation, the nature of the latent reservoir, and its potential for reactivation in the presence and absence of sex hormones. Aim 3: Define the mechanism and cell source of sex hormone modulation of viral replication in vitro. The proposed experiments will fill a significant gap in our understanding of the mechanisms underlying observed differences in HIV-1 disease course and comorbidities between men and women, an important question at a time when sex differences are clearly defining distinct disease outcomes in various disease settings.