# SMC1A/3 cohesin complex-mediated silencing of unintegrated HIV-1 DNA and the antagonism by Vpr

> **NIH NIH R21** · UNIVERSITY OF ROCHESTER · 2024 · $192,500

## Abstract

ABSTRACT
Human immunodeficiency virus (HIV-1) infection can lead to the deadly disease acquired immunodeficiency
syndrome (AIDS). During the natural infection of HIV-1, some viral DNAs are integrated into host genome, but
the vast majority of viral DNAs exist in an unintegrated state. Transcriptional regulation of unintegrated HIV-1
DNA plays important roles in HIV-1 infection and pathogenesis. In contrast to the robust viral gene expression
from integrated viral DNA, the extrachromosomal, unintegrated viral DNAs are very poorly transcribed. The exact
mechanisms for the silencing of unintegrated HIV-1 DNA are not well understood, which constitutes a major
knowledge gap in HIV-1 research. HIV-1 accessory protein Vpr enhances viral gene expression from
unintegrated HIV-1 DNA by targeting host proteins for degradation. In search for Vpr target host factor(s) that
can silence unintegrated HIV-1 DNA, we have performed a CRISPR-Cas9 knockout screening of Vpr target
genes and identified NS1BP. We also found that NS1BP-interacting partner, the SMC1A/3 cohesin complex, is
required for the silencing of unintegrated HIV-1 DNA. We hypothesize that NS1BP acts as a cofactor to facilitate
the loading of the SMC1A/3 cohesin complex on viral DNA, which results in viral chromatin compaction and gene
suppression, and Vpr-mediated degradation of NS1BP results in the dissociation of the cohesin complex from
viral DNA, which consequently depresses the silencing of unintegrated HIV-1 DNA. In this project, we will
determine the mechanism by which NS1BP and the SMC1A/3 cohesin complex mediate the silencing of
unintegrated HIV-1 DNA (Aim 1), and elucidate the mechanism by which Vpr antagonizes the silencing mediated
by NS1BP and the cohesin complex (Aim 2). Our proposed studies will significantly extend our understanding of
the molecular mechanism for the transcriptional regulation of unintegrated HIV-1 DNA and provide new
information regarding the epigenetic silencing of HIV-1 DNA. In the long term, these studies will provide new
targets and strategies for the cure of HIV-1 infection.

## Key facts

- **NIH application ID:** 10908666
- **Project number:** 5R21AI174848-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Yiping Zhu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $192,500
- **Award type:** 5
- **Project period:** 2023-08-16 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908666

## Citation

> US National Institutes of Health, RePORTER application 10908666, SMC1A/3 cohesin complex-mediated silencing of unintegrated HIV-1 DNA and the antagonism by Vpr (5R21AI174848-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10908666. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*