# A chemical genetics approach for studies of HIV-1 latency

> **NIH NIH R21** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $205,000

## Abstract

PROJECT SUMMARY
 Elimination of integrated, replication-competent HIV-1 proviruses from host genomes persisting despite
suppressive anti-retroviral therapy (ART) is the major roadblock to a functional cure. Cells harboring these types
of proviruses produce marginal levels of viral products thereby becoming refractory to immune surveillance
mechanisms. This lack of detection by the immune system, in addition to its increased growth potential, due to
homeostatic proliferation and clonal expansion, extend the lifespan of latently infected cells generating a
persistent reservoir. There is enormous enthusiasm for the potential of precision therapies targeting the latent
reservoir in clinical settings. To achieve this major biomedical goal, we must first discover host factors dictating
reservoir persistence and viral latency maintenance and reactivation before we can leverage this knowledge for
clinical intervention. While previous studies have used several genetic approaches to examine host factor’s
involvement, they hold the intrinsic problem of not allowing to distinguish between direct and indirect effects.
This is a significant issue because one must first define the host factor’s primary function(s) in HIV-1 latency
control to then illuminate the most appropriate approaches for therapeutic intervention.
 In this exploratory and developmental R21 grant application, we circumvent previous issues by
implementing a novel chemical genetics (dTAG) approach to acutely eliminate the expression of a set of host
chromatin regulators (Histone Lysine Methyl Transferases) to assess their roles in HIV-1 proviral latency
maintenance and reactivation. We will first endogenously tag these factors in CD4+ T cell models of latency that
recapitulate the biology of viral persistence in patients. We will then select prioritized candidates for cross-
validation in primary CD4+ T cell models of latency and aviremic patient samples obtained from the UT
Southwestern/Parkland HIV-1 Clinic. If successful, our studies will fill a void in our understanding of HIV-1 latency
biology by describing new basic science and elucidating the most appropriate Histone Lysine Methyl
Transferases for pilot translational studies. Future studies beyond the scope of this focused grant application
will examine the clinical relevance of these host chromatin regulators and devise appropriate therapeutic
interventions.

## Key facts

- **NIH application ID:** 10795925
- **Project number:** 5R21AI175042-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Ivan D'Orso
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $205,000
- **Award type:** 5
- **Project period:** 2023-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795925

## Citation

> US National Institutes of Health, RePORTER application 10795925, A chemical genetics approach for studies of HIV-1 latency (5R21AI175042-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10795925. Licensed CC0.

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