# Elucidating mechanisms of HIV-1 mucosal transmission

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2022 · —

## Abstract

Project Summary/Abstract
HIV/AIDS has spread relentlessly since it was first identified in 1983, causing one of the most devastating
pandemics in human history. Historical accounts of infectious diseases show that they can have a major
impact on U.S. Armed Forces. With 34 million individuals infected worldwide, HIV-1 poses a significant and
persistent threat to force readiness and the stability of many nation-states. The incidence of HIV/AIDS infection
among U.S. service personnel is significant and the risk of exposure to HIV-1 by heterosexual intercourse
among veterans and service personnel is much greater. Heterosexual HIV-1 transmission from men to women
accounts for the majority of new infections worldwide, and notably, women are entering into military service at
an increasing rate. The discovery of effective prevention modalities for women is hindered by a lack of basic
information about early virus-host interactions in the female genital tract mucosa that underlie the acquisition of
HIV-1 infection. Non-human primate (NHP) models of HIV/SIV transmission indicate that macrophages and
predominantly CD4 T cells become infected within the first few days after high-dose intravaginal challenge.
The observation of early CD4 T cell infection seemed consistent with subsequent published work indicating
transmitted/founder (TF) viruses generally exhibit low to moderate tropism for monocyte-derived macrophages
(MDM). However, recent published and unpublished data (Preliminary Studies) would argue that this central
question regarding HIV-1 transmission biology, and the role of macrophages in particular, warrants additional
investigation. Our central hypothesis is that cervical macrophages are required to drive HIV-1 replication and
spread in the cervical mucosa. Our corollary hypothesis, though beyond the immediate scope of this
application, is that cervical macrophages (cMφs) are required for expansion and spread of HIV-1 infection
beyond initial foci of infected CD4 T cell in the mucosa, and thus represent an underlying determinant of
mucosal HIV-1 heterosexual transmission in women. To interrogate this central hypothesis, we propose the
following specific aims: (1) To characterize the dynamics of HIV-1 infection and replication in human cervical
explant tissue; (2) To determine the spatiotemporal relationships between uninfected and HIV-1 infected cMφs
and CD4 T lymphocytes in cervical tissue in situ; and (3) To identify cellular determinants of cMφs
susceptibility to HIV-1 infection. Our research promise to elucidate critical virus-host interactions that underlie
the establishment of HIV-1 infection in the female mucosal genital tract. Validation of our central hypothesis
would impart a paradigm shift in the field, and implicate cMφs as a viable early target for the discovery of new
HIV/AIDS prevention strategies.

## Key facts

- **NIH application ID:** 10428455
- **Project number:** 5I01BX004547-03
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** JOHN Christopher KAPPES
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-01-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428455

## Citation

> US National Institutes of Health, RePORTER application 10428455, Elucidating mechanisms of HIV-1 mucosal transmission (5I01BX004547-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10428455. Licensed CC0.

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