# Targeting HIV-1 RNA modifications in latently infected CD4+ T cells for therapeutic development

> **NIH NIH R61** · UNIVERSITY OF IOWA · 2024 · $699,921

## Abstract

Project Summary/Abstract
Despite highly effective anti-retroviral therapy (ART), the latent HIV-1 reservoir in resting CD4+ T cells is the
major barrier to a functional cure of HIV-1 infection. Our overall objectives of this R61/R33 bi-phasic project are:
to understand the mechanisms of post-transcriptional regulation of HIV-1 RNA in HIV-1-infected individuals who
are on ART (Exploratory R61 phase), and to develop a novel therapeutic strategy to alter RNA post-
transcriptional modifications as a potential therapeutic platform for inhibiting HIV-1 replication (Developmental
R33 phase).
Our multidisciplinary group is uniquely poised to address several key questions highlighted in this funding
opportunity. My lab was among three groups that independently discovered that N6-methyladenosine (m6A)
modifications of HIV-1 RNA modulate viral replication in CD4+ T cells in vitro. Using CD4+ T cell lines and
primary CD4+ T cells from healthy donors, we investigated the mechanisms by which m6A modifications
modulate HIV-1 infection. We also found that m6A modifications of HIV-1 RNA inhibit innate antiviral immune
responses in primary macrophages from healthy donors. Our in vitro studies suggested that m6A modifications
of HIV-1 RNA play a critical role in viral replication and innate immune responses to viral infection. However, the
role of m6A modifications of HIV-1 RNA in regulating viral replication in HIV-1-infected individuals on ART
remains unknown. We aim to fill this important knowledge gap and to translate the findings into potential anti-
HIV-1 therapeutics.
We hypothesize that m6A modifications of HIV-1 RNA help establish and maintain viral latency in CD4+ T cells
and avoid innate antiviral immune responses in HIV-1 infected individuals on ART. To test this hypothesis and
to facilitate the development of a novel strategy for HIV-1 cure, we designed three specific aims in two phases:
(1) R61 phase (years 1-3): Aim 1. To determine m6A profile of HIV-1 RNA in subsets of CD4+ T cells from ART-
treated patients; Aim 2. To identify cellular targets in the m6A pathway important for HIV-1 reactivation in primary
CD4+ T cells; and (2) R33 phase (years 4-5): Aim 3. To examine anti-HIV-1 effects of small molecules inhibiting
m6A modifications in primary CD4+ T cells.
Overall Impact: These studies will reveal how m6A modifications of HIV-1 RNA regulate viral latency in ART-
treated patients. The studies in the R61 phase will define new mechanisms of HIV-1 persistence and identify
potential therapeutic targets. The R33 phase study will develop an m6A-specific strategy to inhibit HIV-1
replication in primary CD4+ T cells.

## Key facts

- **NIH application ID:** 10811788
- **Project number:** 5R61AI169659-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Li Wu
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $699,921
- **Award type:** 5
- **Project period:** 2022-04-01 → 2025-05-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10811788

## Citation

> US National Institutes of Health, RePORTER application 10811788, Targeting HIV-1 RNA modifications in latently infected CD4+ T cells for therapeutic development (5R61AI169659-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10811788. Licensed CC0.

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