Impact of Gender Affirming Hormone Therapy on HIV Viral Dynamics and Immune Responses in Transgender Women

Summary/Abstract Transgender women are at elevated risk for acquisition of HIV, but there is little population-specific data to address whether there are specific features of HIV immunopathogenesis or reservoir maintenance among these individuals. Multiple lines of data indicate significant differences between cisgender women and men with lower levels of setpoint viral load, lower levels of residual viral activity and different patterns of immune activation in response to HIV in cisgender women. Data also indicate that sex steroid hormone exposure contributes to these differences, including a direct suppressive effect of estradiol on HIV latency reversal. These data suggest that gender affirming hormone therapy may impact HIV reservoir features and immune responses in transgender women, but this question has not been directly studied. In this proposal, we address this knowledge gap, leveraging two unique cohorts of transgender women to explore the impact of hormone therapy on measures of the HIV reservoir and immune/inflammatory features. Our first cohort is an existing cross-sectional cohort of TW (n=120) who are evenly divided by HIV serostatus and current hormone exposure; this cohort specifically addresses the impact of sex steroid hormone exposure and gender identity with and without concurrent HIV. Our second cohort is derived from a ACTG 5403, a clinical trial currently enrolling TW living with HIV (TWLH) on suppressive antiretroviral therapy who have been off hormonal therapy. Participants (N=90) initiate a standardized protocol for titration of estrogen therapy with outcomes focused on pharmacokinetic interactions with ART and participant satisfaction. Blood samples (viable cells and plasma) are collected and stored for the virologic, and immune assays described in this proposal. With these two cohorts we will explore three specific aims: 1. Explore the impact of estradiol therapy on measures of the HIV reservoir size, activity, intactness, integration site and clonality. 2. Characterize the impact of HIV and hormone therapy on immune cell profiles by flow cytometry, single cell transcriptomic profiling and plasma inflammatory proteome. 3. Investigate the impact of hormone therapy on metabolic features in the plasma proteome and by cellular energy dependence assays. These three complementary aims with large and well-characterized cohorts will allow us to define the impact of hormone therapy on HIV reservoir and immune cell dynamics and to explore the potential mechanistic role of immune metabolism in some of these effects.