# Overcoming HIV-1 transcriptional latency in unresponsive CD4 T cells

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $647,889

## Abstract

ABSTRACT
 Latent HIV-1 infection has been recognized as a major obstacle to the development of a curative HIV-1
therapy, but host cell-virus interactions that control latent infection are still ill defined. Key to this application is
the realization that the host cells of latent HIV-1 infection events are actually phenotypically altered in a manner
that (i) forces the virus into a latent state and that (ii) renders the host cells unresponsive to stimulation,
thereby preventing efficient therapeutic induction of HIV-1 reactivation. These changes go beyond a simple
quiescent state that is characteristic for functional memory T cells. This proposal will extend on these findings
and seek to address three major roadblocks in the field of HIV latency research. Roadblock #1 (Aim 1)
concerns our inability to identify biomarkers that specifically define T cell sub-populations in which latently
infected T cells are highly enriched. Such biomarkers would allow us to detail the molecular biology of the host
cell state that enables and maintains latent HIV-1 infection. Leading to this application, we found that the
intracellular changes allowing latent HIV-1 infected to persist are associated with a unique CD4+CD28–
CD9+CD151+ phenotype, a T cell phenotype that also demarcates a small CD4 T cell sub-population that is
increased in HIV patients on ART. We already demonstrate that CD151 expression by itself is associated with
reservoir capacity. We will now detail the viral reservoir capacity of T cell sub-populations described by CD28,
CD151 and CD9 expression. Roadblock #2 (Aim 2) addressed in this application is the question how the
intracellular changes observed in host cells of latent HIV infection events act (i) to control HIV transcription and
and (ii) to suppress T cell responsiveness. In addition to the proposed research on host-cell factors/networks
controlling latent HIV infection, we already have identified several targets/interaction networks that control
latent infection and that will be immediately probed. We will further address roadblock #3 (Aim 3), the question
why stimulation of ex vivo T cell material from HIV patients seems to only trigger HIV-1 reactivation in a small
fraction of the latently HIV-infected cells. Based on our results, we predict that T cell subpopulations described
by differential CD28, CD9 and CD151 expression patterns, will exhibit varying levels of unresponsiveness to
stimulation, allowing latent HIV infection to persist with different efficacies. Based on the results we have
obtained leading to this application and the additional results we will generate, we will immediately begin to
rationally design compound-based intervention strategies that would (i) first reconstitute T cell responsiveness
in reservoir populations and then (ii) trigger efficient HIV reactivation, a prerequisite for any HIV-1 eradication
strategy and the ultimate goal of this application.

## Key facts

- **NIH application ID:** 9980780
- **Project number:** 5R01AI122842-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** OLAF KUTSCH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $647,889
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980780

## Citation

> US National Institutes of Health, RePORTER application 9980780, Overcoming HIV-1 transcriptional latency in unresponsive CD4 T cells (5R01AI122842-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980780. Licensed CC0.

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