PROJECT SUMMARY
One million individuals in the United States identify as transgender (0.39% of population), of which 90% are
either on gender-affirming hormone therapy (GAHT) or considering starting GAHT. Understanding how
feminizing GAHT (estradiol) and masculinizing GAHT (testosterone) influence immune function is imperative,
considering that (i) transgender women have a significantly increased prevalence of Human Immunodeficiency
Virus (HIV) infection worldwide and (ii) little is known about how GAHT influences immune function or
susceptibility to infections.
To address this gap in knowledge, our team will combine established state-of-the-art systems immunology
approaches to a completed longitudinal cohort of transgender women before and during GAHT. We previously
used this longitudinal model to show that both feminizing and masculinizing GAHT induced DNA methylation
changes at specific genomic loci in whole peripheral blood, some of which were previously associated with
puberty or pregnancy.
In the first three aims of this project, we will use viably stored peripheral blood mononuclear cells from
transgender women at baseline, and 3 and 6 months following GAHT. By applying a systems immunology
approach, we first seek to establish how GAHT changes the circulating immune profile and plasma metabolites,
both of which are predictors of response to infection and vaccines. Next, innate, and adaptive immune function
will be assessed through in vitro stimulation with a range of microbial and viral microbes, specifically HIV,
followed by cytokine assays. Finally, in Aim 3 we will map the underlying epigenomic profile of specific immune
cell types, by profiling active histone modifications and open chromatin at single cell level. Together, the above
approach will identify the key molecular drivers of altered immune function in response to GAHT and generate
new hypotheses for further study. Ultimately, understanding how GAHT alters the molecular biology of immune
cells will open new avenues to therapeutic intervention in cases where immune function is compromised
because of GAHT.
In aim 4, we will use our established longitudinal GAHT recruitment strategy to establish a cohort of transgender
individuals with extensive biospecimen collection. This will allow us to explore the effects of GAHT on the vaginal
and fecal microbiota and stress, which are known modulators of immunity. Once established, this longitudinal
cohort will provide opportunities to apply a range of state-of-the-art molecular and immunophenotyping
techniques to understand if and how GAHT affects susceptibility to HIV infection.
