# Defining the regulation of double-strand DNA break repair by HIV Vpr

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $371,551

## Abstract

PROJECT SUMMARY / ABSTRACT
HIV presents a major obstacle to human health, particularly in developing nations. Large strides have been made
in understanding the basic molecular biology of HIV, which have led to advances in the development and success
of antiretroviral therapies. Yet despite this knowledge, there are still many aspects of HIV biology which we do
not understand. If we are to ever truly cure individuals of HIV, we must first fully understand the molecular
mechanisms of viral replication to develop novel therapies that take advantage of essential steps in this lifecycle.
One such aspect of HIV biology that has remained a mystery despite decades of research is the accessory gene
Vpr. Vpr is evolutionarily conserved and important for pathogenesis in vivo, yet no clear role for Vpr in viral
replication has been defined. An emerging property of Vpr-associated phenotypes is engagement of the DNA
damage response (DDR). The DDR is a signaling cascade that is vital to ensuring the fidelity of the host genome
in the presence of genotoxic stress. Growing evidence has emphasized the importance of both activation and
repression of the host DDR by diverse DNA and RNA viruses. However, precisely how and why Vpr engages
the DDR is unclear.
We have recently begun to bridge this gap in knowledge by identifying that Vpr both activates and represses the
DDR at multiple steps. Specifically, we have found that Vpr represses the ability of the cell to repair double-
strand DNA breaks via homologous recombination (HR) and non-homologous end joining (NHEJ). Based on our
preliminary data, we hypothesize that repression of double-strand DNA break repair is central to the primary
function of Vpr. Moreover, we propose that the inability of Vpr-expressing cells to repair damaged DNA
represents a tractable means to selectively deplete HIV+ cells via synthetic lethality with genotoxic agents that
induce low levels of additional DNA damage. We will take a combined molecular, proteomic, and evolutionary
approach to directly test our hypotheses. Success of our proposed research will define the primary role of Vpr,
it will elucidate how the DDR regulates HIV replication, and it will provide a novel means to treat HIV+ individuals
and clear infected cells.

## Key facts

- **NIH application ID:** 9931157
- **Project number:** 5R01AI147837-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Oliver I Fregoso
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $371,551
- **Award type:** 5
- **Project period:** 2019-05-21 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931157

## Citation

> US National Institutes of Health, RePORTER application 9931157, Defining the regulation of double-strand DNA break repair by HIV Vpr (5R01AI147837-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9931157. Licensed CC0.

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