# HIV Vpr, CRL4.DCAF1 E3 ligase and their targets

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $450,552

## Abstract

PROJECT SUMMARY
Intrinsic immunity to HIV is counteracted by accessory virulence factors, which, typically, reprogram E3 Ub
ligases to remove HIV restriction factors from infected cells by targeting them for degradation by proteasome.
Indeed, the studies of HIV accessory proteins have led to the identification of major HIV restriction factors,
which in turn revealed new anti-viral mechanisms. HIV-1 Vpr accessory protein binds to CRL4DCAF1 E3 ubiquitin
ligase and uses this enzyme to antagonize specific postreplication DNA repair proteins, such as uracil DNA
glycosylase (UNG2), HLTF DNA helicase and MUS81 structure specific nuclease. Furthermore, we recently
identified Exonuclease 1 (Exo1) DNA repair protein as a novel target of the hijacked by Vpr CRL4DCAF1 E3.
HIV-1 Vpr was also reported to bind DNA processing proteins, which associate with a large protein complex
assembled on SLX4 scaffold that connects to diverse DNA repair pathways. The fact that Vpr interacts with
and disrupts multiple aspects of the cellular DNA repair machinery is intriguing, as there is little doubt that Vpr
antagonism with this machinery should ultimately benefit HIV-1. Nevertheless, very little is known about how
the DNA repair proteins targeted by Vpr impinge on HIV-1 replication and the underlying mechanism(s) have
not been thoroughly investigated.
 This application focuses on how DNA repair proteins antagonized by Vpr and those controlled by the
SLX4 scaffold impinge on HIV-1 replication. We recently confirmed that HIV-1 Vpr promotes HIV-1 replication
in dividing T cells and linked this effect to Vpr's ability to antagonize DNA repair proteins via CRL4DCAF1 E3. We
also demonstrated that an as yet unidentified component controlled by the SLX4 scaffold inhibits HIV-1
infection. We hypothesize that the above DNA repair proteins act on intermediates in the synthesis of the
double stranded HIV-1 cDNA prior to, or following provirus integration, thereby inhibiting HIV-1 infection, and
that some of these effects are counteracted by HIV-1 Vpr. Here we propose to characterize the interactions
between DNA repair proteins targeted by Vpr, as well as those controlled by the SLX4 scaffold, with the HIV-1
cDNA and elucidate how they inhibit HIV-1 replication. In particular, we will characterize the actions of DNA
repair proteins that are antagonized by Vpr to stimulate HIV-1 replication (SA1), identify steps that the SLX4
complex and Vpr-CRL4DCAF1 E3-targeted HLTF and Exo1 act on (SA2), and characterize DNA repair pathways
and activities that inhibit HIV-1 (SA3). Overall, this application will describe the molecular mechanisms
mediating the inhibition of HIV-1 replication in dividing T lymphocytes by cellular DNA repair machinery, and
those used by HIV-1 Vpr to antagonize the inhibition.

## Key facts

- **NIH application ID:** 9986658
- **Project number:** 5R01AI150469-04
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Jacek Skowronski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $450,552
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986658

## Citation

> US National Institutes of Health, RePORTER application 9986658, HIV Vpr, CRL4.DCAF1 E3 ligase and their targets (5R01AI150469-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9986658. Licensed CC0.

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