# Aging compromises neutrophil-mediated innate protection against HIV in the human female genital tract.

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2020 · $407,073

## Abstract

PROJECT SUMMARY
The main route for HIV acquisition in women of all ages is sexual transmission. While younger women (15–24
years) are at high risk for HIV infection in endemic areas, an increasing incidence of new HIV infections in older
women (age >50 years) is observed worldwide. Yet, the mucosal events that lead to the prevention or acquisition
of HIV and how mucosal protection is affected with aging are largely unknown. Thus, it is critical to identify the
early mucosal mechanisms that prevent HIV infection of target cells and how this protection is modified with
aging, in order to develop effective preventive approaches for younger and older women.
Neutrophils are abundant throughout the female reproductive tract (FRT) in pre- and post-menopausal women
and are distinct from neutrophils present in blood. However, despite their key location at mucosal surfaces in the
FRT (the main site for HIV exposure in women) and their critical role in innate immunity, the extent to which FRT
neutrophils contribute to protection against HIV infection in women is unknown. The PI's research group recently
discovered that, neutrophils from the human FRT undergo NETosis in response to HIV, which prevents infection
of CD4+ T cells. NETosis is a phenomenon characterized by the release of Neutrophil Extracellular Traps (or
NETs), which are segments of DNA associated with granular proteins with antimicrobial activity. The research
team further found that the magnitude of HIV-induced NETosis is significantly reduced in post-menopausal
women. Based on these preliminary results, the hypothesis being tested here is that HIV-induced NETosis of
neutrophils represents a previously unrecognized level of mucosal innate protection against HIV in the FRT that
is compromised with aging. This hypothesis will be tested through three specific aims. First, experimental studies
will be performed to determine how FRT NETs prevent HIV infection (Aim 1); then, to identify the mechanisms
by which HIV triggers NETosis of FRT neutrophils (Aim 2); and, finally, to elucidate why HIV-induced NETosis is
impaired in post-menopausal women (Aim 3).
The proposed studies will investigate purified neutrophils isolated from different sites in the FRT (endometrium,
endocervix, and ectocervix). NETosis will be assessed with a quantitative, high-throughput, time-lapse imaging
approach. The overall objective will be to determine how NETs contribute to anti-HIV mucosal protection in the
FRT. It is expected that these studies will result in the identification of NETosis as a previously unrecognized
form of immune protection against HIV in the FRT, one that has the potential of leading to a paradigm shift in
our understanding of HIV acquisition. The identification of the mechanisms triggering NETosis in response to
HIV, and how these mechanisms are compromised in older women, will have significant translational impact and
serve as the foundation for novel prevention approaches for women of all ages.

## Key facts

- **NIH application ID:** 9993980
- **Project number:** 5R01AG060801-03
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Marta Rodriguez Garcia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $407,073
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993980

## Citation

> US National Institutes of Health, RePORTER application 9993980, Aging compromises neutrophil-mediated innate protection against HIV in the human female genital tract. (5R01AG060801-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9993980. Licensed CC0.

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