# A nonhuman primate model to study the immunological effects of feminizing hormone therapy in transgender women

> **NIH NIH R21** · SCRIPPS FLORIDA · 2022 · $180,415

## Abstract

HIV/AIDS thrives in the margins of society, where low education, unstable housing, and poverty heighten
people's vulnerability to HIV. No population is more affected by these social injustices than transgender persons.
A case in point is transgender women (TGW}-individuals who were assigned a male sex at birth but express
their gender along a feminine spectrum. Sadly, TGW have some of the highest concentrated HIV epidemics in
the world, with a pooled global prevalence of 19% and a 49-fold higher odds ratio of acquiring HIV than non-transgender
adults. A key part of gender affirmation in TGW is feminizing hormone therapy (FHT), of which the
main drug is the hormone estradiol. Although the physical female traits triggered by FHT are well established,
less is known about the immunological effects of FHT in TGW. It is noteworthy that estradiol can modulate
immune responses in many ways, including by upregulating CCR5 expression on CD4+ T-cells. Since activated
CCR5+ CD4+ T-cells are highly permissive to HIV infection, a better understanding of how FHT impacts the
male immune system may provide new insights into how to prevent HIV infection in TGW. In this regard, here
we will model FHT in nonhuman primates to prospectively address two knowledge gaps about the impact of FHT
on the male immune system. 1) Does FHT increase the availability of HIV-susceptible CD4+ T-cells in vivo? To
answer this question, we will use flow cytometry to assess the frequency and phenotype of memory CD4+ Teens
in blood and gut biopsies from male rhesus macaques receiving FHT (Group 1) or placebo (Group 2). By
comparing the levels of activated CD4+ T-cells between animals in Groups 1 and 2, this analysis will reveal
whether FHT modulates a crucial marker of HIV susceptibility in biological males. 2) Does FHT interfere with
adeno-associated virus (AAV}-vectored immunoprophylaxis? Considering TGW's high risk of acquiring HIV, they
stand to benefit greatly from AAV-mediated delivery of immunoglobulins as this approach can provide durable
anti-HIV immunity after a one-time administration. Indeed, a single dose of an AAV vector encoding the potent
and extremely broad HIV entry inhibitor eCD4-lg resulted in persistent expression of eCD4-lg and protection
against stringent immunodeficiency virus challenges in rhesus macaques. However, given the
immunoenhancing properties of estradiol, FHT may undermine AAV-driven eCD4-lg expression in TGW by
amplifying host anti-drug antibodies (ADAs}-a major limiting factor for AAV delivery of biologics. To address this
possibility, all animals in Groups 1 and 2 will be inoculated with AAV/eCD4-lg after 6 months of FHT or placebo
therapy. We will then compare their serum levels of eCD4-lg and ADAs to determine the impact of FHT on AAV-mediated delivery of eCD4-lg in males. Ultimately, the experiments proposed here will begin to uncover how
FHT can affect HIV susceptibility and the outcome of immune interventions in TGW.

## Key facts

- **NIH application ID:** 10307630
- **Project number:** 5R21AI157929-02
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Mauricio A Martins
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $180,415
- **Award type:** 5
- **Project period:** 2020-12-01 → 2022-04-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10307630

## Citation

> US National Institutes of Health, RePORTER application 10307630, A nonhuman primate model to study the immunological effects of feminizing hormone therapy in transgender women (5R21AI157929-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10307630. Licensed CC0.

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