# Identifying drivers of genital inflammation and HIV acquisition in women living in sub-Saharan Africa

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $819,227

## Abstract

PROJECT SUMMARY
The majority of HIV worldwide is transmitted following heterosexual intercourse and women are twice as likely
to contract HIV from heterosexual sex than men. Mucosal tissues in the female genital tract (FGT) therefore
represent the frontline of transmission since they are the site at which HIV infection is first established in most
incident cases. FGT microbiota composed of diverse communities of bacteria with low Lactobacillus abundance
are associated with elevated mucosal inflammation, increased numbers of cervical HIV target cells, and over
four-fold higher risk of HIV acquisition. In our prior work with the FRESH (Females Rising through Education,
Support and Health) study, we demonstrated that these high-risk bacterial communities are present in over 60%
of young, healthy, black South African women. The specific mechanisms by which vaginal microbiota contribute
to HIV acquisition risk remain unknown. To address these knowledge gaps, we will utilize samples from 1200
FRESH participants with longitudinal blood and genital sampling, including pre- and post-infection samples from
102 women who went on to acquire HIV. In Aim 1.1 we will generate multi-omics datasets characterizing vaginal
microbiota utilizing metagenomics, metatranscriptomics, fungal internally transcribed spacer (ITS) sequencing,
culturomics, microbial whole genome sequencing (WGS), and metabolomics. We will complement this in Aim
1.2 with a comprehensive characterization of the host FGT mucosal environment by assessing genital
inflammatory chemokines and cytokines, cervical flow cytometric cell phenotype, and cervical single cell RNA
sequencing (scRNAseq) profiles, combined with in-depth behavioral and demographic metadata. These complex
multi-omics datasets and metadata will then be integrated in Aim 1.3 following critical quality control,
transformation, and imputation of data from each modality. Modern supervised integration techniques will be
used to identify multi-omics profiles predictive of genital inflammation and HIV acquisition. Novel candidate
vaginal bacterial strains, functions, and/or metabolites will then be validated in Aim 2 using innovative in vitro
and in vivo models, including an organ-on-a-chip model, cervical and vaginal organoids, and a humanized mouse
model. [In addition, we will test candidate features and hypotheses based upon our extensive preliminary data
and established work in the field]. Overall, this project will identify specific bacterial strains and molecules, along
with host cellular lineages and sensing pathways, that mediate microbiota-induced genital inflammation and
increased HIV acquisition risk. It will also validate much needed novel model systems that test the interactions
of microbiota, host, and HIV to provide critical resources to develop the mechanistic understanding needed to
advance the field.

## Key facts

- **NIH application ID:** 11007561
- **Project number:** 1R01AI184095-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Scott A. Handley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $819,227
- **Award type:** 1
- **Project period:** 2024-08-02 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11007561

## Citation

> US National Institutes of Health, RePORTER application 11007561, Identifying drivers of genital inflammation and HIV acquisition in women living in sub-Saharan Africa (1R01AI184095-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/11007561. Licensed CC0.

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