# Molecular Mechanisms of HIV Latency

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2021 · $68,909

## Abstract

PROJECT SUMMARY FROM PARENT AWARD
Post-integration viral latency is a major barrier to eradicating HIV-1 infection. The current theoretical
paradigm for eliminating the viral reservoir is known as ‘Shock and Kill’, reactivation of latent virus
using non-targeted small molecules. Key hurdles to this approach have recently emerged such as
inefficient and/or stochastic viral reactivation, avoidance of global T-cell activation, and limited cellular
death upon re-activation. It is also becoming apparent that our understanding of the molecular
mechanisms of HIV latency are fragmentary and in particular the relevance of drugs of abuse on the
initiation and maintenance of HIV latency.
Here, we propose to explore on a genomic scale the landscape of cellular factors that regulate HIV
latency establishment and maintenance and their relationship to drugs of abuse. Our exploration will
be based on validating a recently completed genome scale shRNA screen for genes that control
latency maintenance and reactivation. We propose to expand this screen using the novel CRISPR-
Cas9 technology based on targeting via a guide RNA fusion proteins that either activate (CRISRa) or
inhibit (CRISPRi) gene expression. These screens will focus on the mTOR pathway and on
methamphetamine as we have recently uncovered evidence that they may act independently or
together to modulate the reactivation of latent HIV. We will validate and mechanistically explore both
pathways and other top hits in primary CD4 T cells and in cells from HIV-infected patients.
We also propose to further develop and exploit new dual-fluorescence reporter HIV-1 genomes to
identify, quantify, and purify latently infected cells in their native state, without inducing viral
reactivation. This new latency model will allow us to study the effect of drugs of abuse, particularly
methamphetamine, on the establishment and maintenance of latency in primary human lymphoid
cells and to study the very earliest mechanisms of HIV-1 latency establishment. By combining the
power of our dual-labeled latency model with high-resolution single-cell systems-biology techniques,
we are uniquely suited to map out the cellular regulatory networks that control HIV latency and the
role of drugs of abuse in this process.

## Key facts

- **NIH application ID:** 10308273
- **Project number:** 3R01DA041742-05S1
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Eric M. Verdin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $68,909
- **Award type:** 3
- **Project period:** 2016-04-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308273

## Citation

> US National Institutes of Health, RePORTER application 10308273, Molecular Mechanisms of HIV Latency (3R01DA041742-05S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10308273. Licensed CC0.

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