# Host protein targets of HIV-1 Vpr in gene expression, cell cycle and innate immunity

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2022 · $423,750

## Abstract

The role and mechanism of action of Vpr (Viral Protein R), an accessory protein encoded by HIV-
1, has been enigmatic for decades. Vpr causes cell cycle arrest at G2/M, triggers a DNA damage
response, and enhances viral gene expression. It exerts these activities by targeting host
protein(s) for degradation, hijacking cullin4-based E3 ubiquitin ligase complex (CRL4) to induce
their depletion. We recently identified a host protein CCDC137, also known as cPERP-B, as a
key target protein depleted by Vpr in a CRL4 complex dependent manner. Specifically, CCDC137
depletion by RNA interference recapitulates the aforementioned effects of Vpr on host and virus.
In this project we seek to study the molecular details of how CCDC137 represses HIV-1 gene
expression as well as how it controls cell cycle progression and the DNA damage response. In
Aim 1, we will determine whether CCDC137 depletion is a conserved feature of Vpr proteins from
diverse HIV and SIV strains, map the CCDC137 determinants required for Vpr-induced depletion,
and assess the effect of Vpr from diverse viruses on viral gene expression. In addition, we will
define host proteins required for CCDC137 depletion by Vpr. Aim 2 is centered on the
mechanisms of CCDC137-mediated repression of HIV-1 gene expression. We will delineate cis-
acting sequences required for CCDC137-mediated repression and evaluate the effect of
integration and integration site selection on the Vpr/CCDC137-regulated HIV-1 gene expression.
We will also combine screening methods (proteomics, yeast 2-hybrid, and CRISPR functional
screens) to identify CCDC137 interacting cofactor(s) to illuminate the mechanism of how
CCDC137 inhibits HIV-1 gene expression. In Aim 3 we will investigate how CCDC137 prevents
DNA damage response and controls cell cycle progression. In particular, we will determine
whether CCDC137 protects chromosomal DNA and delineate host factor(s) cooperating with
CCDC137 to modulate the DNA damage response.

## Key facts

- **NIH application ID:** 10468987
- **Project number:** 5R01AI157809-03
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Paul D. Bieniasz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2020-09-17 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468987

## Citation

> US National Institutes of Health, RePORTER application 10468987, Host protein targets of HIV-1 Vpr in gene expression, cell cycle and innate immunity (5R01AI157809-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10468987. Licensed CC0.

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