# Effect of estrogen replacement on postmenopausal ART-associated comorbidity and viral latency

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $818,107

## Abstract

PROJECT SUMMARY
Current antiretroviral therapy (ART) regimens have rendered HIV/AIDS a manageable chronic condition rather
than a fatal disease, and people living with HIV (PLWH) that initiate ART soon after infection can achieve almost
normal life expectancy. This leads to an aging population of PLWH that are increasing subject to a collection of
age-associated diseases, including obesity, diabetes, and cardiovascular disease. In spite of effective control of
viremia, HIV-induced inflammation is incompletely resolved following ART initiation, and this chronic
inflammation leads to a variety of comorbidities, including increased risk for the same age-related diseases.
Women living with HIV (WLWH) now comprise the majority of the global HIV/AIDS population and represent the
preponderance of new cases. However, women are still underrepresented in clinical studies in spite of significant
sex differences in multiple aspects of HIV pathology. As a consequence of the increased survival of PLWH, more
WLWH will now undergo menopause and be subject to a disease burden that reflects age, ART-associated
chronic inflammation, and, in addition, any adverse consequences of postmenopausal estrogen deficiency. The
likely effects of estrogen deficiency will involve changes in systemic metabolic status, white adipose tissue (WAT)
function and control of glucose and lipid metabolism, and suppression of the circulating and tissue latent
reservoirs based on the recent discovery that estrogen receptor-α is a negative regulator of the HIV reservoir.
We hypothesize that estrogen replacement will reduce the scope and severity of ART-associated metabolic
comorbidities and facilitate ART suppression of latent reservoirs in WLWH. We propose to address this
hypothesis using a unique nonhuman primate model of female rhesus macaques infected with a novel barcoded
strain of simian immunodeficiency virus (SIV), then treated with a current ART regimen until full suppression,
followed by ovariectomy and subsequent estrogen deficiency or estrogen replacement by silastic implants.
This hypothesis will be addressed through pursuit of the following specific aims:
Specific Aim 1. Determine the effect of E2 replacement on metabolism and WAT function in an nonhuman
primate (NHP) model of postmenopausal WLWH. Female rhesus macaques will be infected with SIV, treated
with ART until full suppression, and then ovariectomized with subsequent replacement with premenstrual levels
of estrogen or placebo vehicle. Glucose and lipid metabolic parameters and levels of circulating adipocytokines
and WAT immune cell profiles and WAT function will be assessed longitudinally throughout the study.
Specific Aim 2. Determine the effect of E2 replacement on peripheral, secondary lymphoid, and WAT SIV latent
reservoirs. The size, complexity, and clonality of the plasma, cell-associated and inducible, replication-competent
reservoirs will be assessed following modulation of estrogen status using multiple quan...

## Key facts

- **NIH application ID:** 10838559
- **Project number:** 5R01AG071441-04
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Paul Kievit
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $818,107
- **Award type:** 5
- **Project period:** 2021-08-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838559

## Citation

> US National Institutes of Health, RePORTER application 10838559, Effect of estrogen replacement on postmenopausal ART-associated comorbidity and viral latency (5R01AG071441-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10838559. Licensed CC0.

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