# Spatial analysis of tissue immune responses in persistent HIV infection

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $547,137

## Abstract

Improved understanding of the HIV reservoir in tissues is critical to curative efforts. Progress in
understanding the HIV reservoir has been hampered by difficulty to access clinically relevant tissue
samples for HIV cure research. We have overcome this challenge through innovative cohort design and a
long-standing collaboration at the heart of the global HIV epidemic in KwaZulu Natal, South Africa. There
we have established the FRESH (Females Rising through Education, Support and Health) Study that allow
us to access large blood volumes and tissue samples from persons who initiate therapy very early in Fiebig
Stage I-II, some of whom have interrupted therapy during their participation in a bNAB intervention study.
We propose to use samples from these cohorts to determine the barriers to HIV eradication in lymph nodes
and the gut, and to test novel approaches of overcoming these barriers using the lymph-node-on-a-chip
technology. This grant builds on the firm foundation laid by compelling data generated in the previous
funding period, including the discovery that HIV persists in germinal center T follicular helper cells (GC
TFH) mainly within the B cell follicles (BCFs) even after more than 3 years. We also showed that a stronger
virus specific CD8+ T cell response in LNs is associated with reduced persistence, however, the lack of
cytolytic potential by CD8+ T cells that infiltrate the BCF allows the virus to persist. We will now use the
best-in-class imaging and omics technologies to determine the molecular barriers to HIV eradication in the
BCFs, testing the hypothesis that HIV induced immune regulatory environment in the BCL mitigates
cytotoxic activity of follicular CD8+ T cells. We will use serial excisional LN, gut biopsies and match
blood samples to identify cellular and signaling processes that impede immune mediated eradication of
HIV in tissues. Additionally, we will create the first known model of the HIV infected human BCF in
vitro using the organ on a chip microfluidics technology and use it to test the impact of IL-15 and IL-10
blockade on enhance CTL mediated eradication of the HIV reservoir the BCF. If successful, these studies
will lead to the discovery of novel therapies for HIV eradication in secondary lymphoid organs which must
be a critical component of an HIV cure strategy.

## Key facts

- **NIH application ID:** 10838764
- **Project number:** 1R01AI181690-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Zaza Mtine Ndhlovu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $547,137
- **Award type:** 1
- **Project period:** 2024-04-29 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838764

## Citation

> US National Institutes of Health, RePORTER application 10838764, Spatial analysis of tissue immune responses in persistent HIV infection (1R01AI181690-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10838764. Licensed CC0.

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