# Barrier integrity, microbiome and HIV target cell interactions in the human male genital tract pre and post circumcision

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $623,966

## Abstract

HIV acquisition in men through penile exposure is one of the least studied aspects of HIV transmission.
Medical Male Circumcision (MMC) has been shown in clinical trials to reduce the risk of HIV infection in
heterosexual men. It is not fully known how MMC works to decrease male heterosexual transmission.
One possible explanation is that the urethral and skin mucosal barriers of the penis change after MMC
to strengthen its defenses against HIV. Another possibility is that the foreskin itself is particularly
vulnerable to HIV, having weaker defenses allow the virus to more easily reach susceptible immune
target cells. This might especially be true when an uncircumcised man has a sexually transmitted infection
(STI) would generate a local immune response and recruitment of susceptible HIV target cells. These
possibilities form the basis of this study which will determine how the penile mucosal barriers change
after MMC. We will recruit several cohorts of sexually active males between 18-35 years old receiving
MMC in Chicago and Cape Town and from an STI clinic in Cape Town. To address the potential role of
STIs, we will also enroll males in Cape Town who are asymptomatically positive for Chlamydia
Trachimonas (CT) or Human Papilloma Virus (HPV). To monitor a changing local environment, we will
follow these participants for 2-6 months after CT treatment or MMC. We will measure changes in penile
skin integrity using in vivo monitoring of trans epithelial water loss (TEWL) and collect foreskins to use in
laboratory-based investigations aimed at identifying factors that may lead to increased HIV susceptibility.
We will also characterize the penile skin and urethral microbiome and characterize inflammation levels
in the urethra. We will explore possible mechanisms for how MMC works to decrease HIV acquisition in
men through three specific aims. Aim 1 will determine how circumcision and asymptomatic STI (CT and
HPV) influence the urethral immune environment and microbiome. In Aim 2, we will compare differences
in the coronal sulcus (CS) microbiome and TEWL pre and post MMC, and assess the potential impact of
asymptomatic CT and HPV infections on these measurements. These findings will be linked to
microbiome and immune changes in the urethra. Finally, in Aim 3, we will compare target cells, barrier
function, structural barrier protein expression, and virus interactions between inner and outer foreskin
and determine if infection with an asymptomatic STI can alter the local mucosal environment. We
therefore hypothesize that the inner foreskin: 1) has greater permeability, 2) has reduced expression of
skin integrity proteins, 3) contains more HIV-1 immune cells and 4) allows for greater HIV attachment
and penetration, than the outer foreskin. These interactions may be influences by the presence of
asymptomatic CT and HPV. Collectively, our results will provide fundamental knowledge to inform
alternative HIV prevention strategies.

## Key facts

- **NIH application ID:** 10236337
- **Project number:** 5R01DK108434-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Thomas Hope
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $623,966
- **Award type:** 5
- **Project period:** 2017-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236337

## Citation

> US National Institutes of Health, RePORTER application 10236337, Barrier integrity, microbiome and HIV target cell interactions in the human male genital tract pre and post circumcision (5R01DK108434-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10236337. Licensed CC0.

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