Impact of gender affirming hormone therapy on immune modulation and HIV infection in transgender young adults

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Project Summary Transgender people have a higher risk of HIV acquisition than cisgender people. Transgender youth are more likely than heterosexual youth to report early onset of sexual activity, have more lifetime sexual partners, and are less likely to use a condom with last intercourse placing them at an increased risk of acquiring HIV. Although behavioral and psychosocial factors lead to a higher HIV risk in transgender people, gender-affirming hormone (GAH) treatment (i.e., testosterone for transgender individuals assigned female at birth (AFAB) or estrogen/antiandrogen for transgender individuals assigned male at birth (AMAB)) may alter biological factors, resulting in increased transmission of HIV. Our goal is to determine immune attributes associated with increased HIV risk in transgender people, with the long-term goal of HIV prevention. Sex hormones are known to modulate the immune response, resulting in changes in host susceptibility to pathogens, vaccine efficacy and drug metabolism. A key gap in knowledge is that the immunological consequences of GAH therapy in transgender populations remains unknown. We have shown that hormonal contraceptive administration alters immune markers for HIV preference and increases susceptibility of CD4+ T cells to HIV in women. Sex hormones also alter the mucosal immune milieu, vaginal microbiome, ex vivo HIV infectivity, and in vitro HIV infection of primary cells. We recently discovered that young adults (aged 18-25) had higher HIV risk immune and ex vivo HIV infection profiles than adult subjects (aged 27-41). Thus, transgender youth may be at particular risk due to age- and GAH (estrogen/antiandrogen or testosterone)-mediated immune attributes that favor HIV infection. Our objective here is to determine the effect of GAH therapy on immune regulation and to identify immune attributes associated with increased HIV susceptibility in young transgender individuals. We hypothesize that GAH therapy alters immune functions that impact HIV infection in the transgender youth. We will conduct a longitudinal study to determine peripheral and mucosal immune responses and ex vivo HIV infection in AFAB and AMAB individuals at baseline and after 1, 3, and 6 months of GAH treatment with low to high concentrations of hormones. In light of recent findings that anti-retroviral therapies are less effective in transgender women, our results will inform both development of better treatments for individuals undergoing hormone therapy and the design of more effective HIV prevention strategies.