# Multifaceted interactions between lentiviral Vif and host molecules for viral infectivity enhancement

> **NIH NIH R37** · YALE UNIVERSITY · 2023 · $37,681

## Abstract

PROJECT DESCRIPTION
The APOBEC3 (A3) family of proteins are cellular cytidine deaminases that suppress human
immunodeficiency virus type 1 (HIV-1) infection by hypermutation of viral reverse transcripts and physically
blocking reverse transcription. To evade this host defense mechanism, HIV-1 expresses the virion infectivity
factor (Vif), which hijacks a cellular E3 ubiquitin ligase complex and targets A3 proteins (A3F/G/H/D) for
proteasome-mediated degradation. Besides degrading A3s, HIV-1 Vif also causes G2 cell cycle arrest by
targeting multiple protein phosphatase 2A (PP2A) regulators (PPP2R5 proteins) for degradation. Adding to the
complexity of Vif-host protein interactions, HIV-1 Vif utilizes the transcription factor CBFβ as a non-canonical
cofactor, while maedi-visna virus (MVV) Vif co-opts the prolyl isomerase cyclophilin A (CypA) instead. Our goal
is to establish the biochemical and structural principles for the multifaceted activities of lentiviral Vif molecules
that recruit cellular factors to degrade host proteins via ubiquitin-proteasome pathways. To achieve our goal,
we will use a combination of biochemical, biophysical, structural biology, and cellular functional techniques. To
establish the mechanisms by which A3 proteins are targeted by the HIV-1 Vif (Aim1), we will determine high-
resolution structures of the A3-Vif-E3 interaction complexes, validate these structures by structure-guided
mutagenesis experiments in vitro and in vivo, and interrogate the molecular determinants of Vif/A3/E3 ligase
assembly and activation. In addition, we will also study the degradation-independent mode of Vif inhibition of
A3 deamination and antiviral activities. To better understand CypA-mediated formation of MVV Vif-E3 ubiquitin
ligase (Aim2), we will assemble MVV Vif/CypA/E3 ligase complexes with or without A3 substrates, determine
their high-resolution structures, and perform biochemical and functional validations of our structural
observations. The influences of capsid proteins on the assembly and activation of MVV Vif-E3 ligase will also
be investigated. To delineate the mechanisms of PPP2R5/PP2A recruitment by lentiviral Vif-E3 ubiquitin
ligases (Aim3), we will investigate the effects of PPP2R5 proteins on the assemblies of the CBFβ-mediated
HIV-1 Vif and CypA-mediated MVV Vif-E3 ligases, obtain high-resolution structures, and perform structure-
guided validations. Our comprehensive research design provides a robust approach that will generate
unprecedented insights into the diverse functions of lentiviral Vif molecules.

## Key facts

- **NIH application ID:** 10600207
- **Project number:** 3R37AI116313-07S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Yong Xiong
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $37,681
- **Award type:** 3
- **Project period:** 2015-06-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10600207

## Citation

> US National Institutes of Health, RePORTER application 10600207, Multifaceted interactions between lentiviral Vif and host molecules for viral infectivity enhancement (3R37AI116313-07S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10600207. Licensed CC0.

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