# Immune Microenvironments That Impact HIV Persistence and Expression During ART

> **NIH NIH R56** · UNIVERSITY OF ARIZONA · 2024 · $153,311

## Abstract

ABSTRACT
A formidable barrier to a cure for HIV-1 infection is the existence of latently infected cells that sporadically
activate HIV transcription during antiretroviral therapy (ART) and reignite widespread virus replication upon
cessation of ART. Viral RNA expressing (vRNA+) cells are detected at low frequencies in secondary lymphoid
tissues (SLT) of people with HIV (PWH) on ART, constitute the major HIV RNA reservoir in the human body,
and are likely the principal source of rebound viremia when ART is stopped. Little is known about the
microenvironment of vRNA+ cells in SLT of PWH during ART. In lymph nodes and spleen from PWH on
prolonged ART the majority of vRNA+ cells reside outside of B cell follicles and only a minority are TFH. We
observed that vRNA+ cells are preferentially located adjacent to B cells not only in follicular, but also in
extrafollicular regions (EF) of SLT in PWH and SIV-infected rhesus macaques on ART; frequencies of B cells in
EF of SLT correlate with frequencies of vRNA+ cells. In an ex vivo tonsil model of HIV infection, germinal
center B cells (GCB) upregulate HIV expression in TFH. Gene expression analysis revealed GCB induce
expression of multiple cytokines including IL-10, pro-survival molecules, and markers of immune activation.
Further studies revealed that upregulation of HIV expression is not confined to GCB, but that multiple subsets
of tonsil B cells upregulate HIV replication in both TFH and non-TFH CD4+ T cells. IL-10 was shown to
augment survival of HIV-expressing cells in the tonsil model, and we observed that the majority of vRNA+ cells
in spleen from two PWH expressed IL-10. We hypothesize that B cells are major drivers of vRNA
expression in CD4+ T cells in secondary lymphoid tissues of PWH on ART through induction of pro-
survival factors, including IL-10, as well as immune activation. In Aim 1, we will determine the location,
phenotype, and microenvironment of vRNA+ cells in spleen, lymph nodes, and ileum of PWH on prolonged
ART using state-of-the-art immunostaining techniques to assess the hypothesis that vRNA+ cells preferentially
exist adjacent to B cells and express pro-survival and activation markers. In Aim 2, we will evaluate the impact
of SLT B cells on HIV expression in non-TFH CD4+ T cells, and evaluate the role of IL-10 and immune
activation using HIV GFP reporter viruses in SLT from people without HIV infection, as well as spleen and
lymph node tissues from people with HIV infection on prolonged ART. In Aim 3 we will determine whether
depletion of B cells leads to reductions in numbers of vRNA+ cells in SLT during ART using SIV-infected
rhesus macaques. Collectively, these studies will provide a wealth of new information on the cells that express
HIV in SLT and factors within their microenvironment that promote or impair HIV expression during ART. This
knowledge could be used to develop strategies to reverse or alternatively enhance viral latency in vivo to
achieve a functional remissio...

## Key facts

- **NIH application ID:** 11118367
- **Project number:** 1R56AI181705-01
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Elizabeth Connick
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $153,311
- **Award type:** 1
- **Project period:** 2024-08-05 → 2024-12-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11118367

## Citation

> US National Institutes of Health, RePORTER application 11118367, Immune Microenvironments That Impact HIV Persistence and Expression During ART (1R56AI181705-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/11118367. Licensed CC0.

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