# Cellular Determinants and Function Consequences of PP2A-B56 Degradation by HIV-1 Vif

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $551,363

## Abstract

PROJECT SUMMARY
The HIV-1 Vif protein is expressed late during infection and has a well-described function to ubiquitinate and
degrade proteins in the APOBEC3 family, thus neutralizing their antiviral activities. More recently, an additional
function of HIV-1 Vif was described by us and others to ubiquitinate and degrade protein phosphatase 2A
holoenzymes containing B56 family regulatory subunits (PP2A-B56). The conservation of Vif-mediated PP2A-
B56 degradation throughout globally circulating HIV-1 subtypes suggests that it is functionally important.
However, there remains a gap in understanding the mechanisms by which PP2A-B56 degradation confers a
fitness advantage to HIV-1. Furthermore, in contrast to APOBEC3 degradation, the host cellular determinants
required for Vif-mediated ubiquitination and degradation of PP2A-B56 are undefined.
In this project, we aim to address these gaps in understanding by defining the cellular determinants and functional
effects of PP2A-B56 degradation by HIV-1 Vif. In Aim 1, we will apply unbiased protein interaction technologies
to determine proteins interacting with PP2A-B56 while it is degraded by Vif. In Aim 2, we will carry out a genome-
wide CRISPR/Cas9 genetic screen to identify genes regulating APOBEC3 and PP2A-B56 degradation. In Aim
3, will test the impact of individual phosphorylation sites regulated by PP2A-B56 in HIV-1 replication in primary
CD4+ T cells. Successful completion of this project will advance understanding of the Vif-PP2A-B56 signaling
axis, potentially leading towards the development of novel classes of antiretroviral therapies that target late
processes of HIV-1 infection.

## Key facts

- **NIH application ID:** 10837857
- **Project number:** 5R01AI167691-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Jeffrey R Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $551,363
- **Award type:** 5
- **Project period:** 2023-05-05 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837857

## Citation

> US National Institutes of Health, RePORTER application 10837857, Cellular Determinants and Function Consequences of PP2A-B56 Degradation by HIV-1 Vif (5R01AI167691-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10837857. Licensed CC0.

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