# Structure and Evolution of APOBEC3-Vif Interactions

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $446,170

## Abstract

Restriction factors are a branch of the innate immune system that potently inhibit viral replication. A number of
viral pathogens encode accessory proteins that can antagonize restriction factors, which allows viral
dissemination in host. Over evolutionary time, restriction factors evolve to escape viral antagonists, limiting the
host range of viruses. In turn, viruses can adapt to these changes and cross species into new hosts by rapid
evolution of accessory proteins. The primate APOBEC3 cytidine deaminases are arguably the most
extensively studied family of restriction factors. They block the spread of retroviruses and retroelements by
hypermutating their genomes and have the potential to inhibit the AIDS virus, HIV-1. However, the HIV-1
accessory protein Vif potently suppresses APOBEC3 enzymes by targeting them for degradation by the host
ubiquitin-proteasome system. Vif is conserved in all existing lentiviruses, including those of primate origin such
as SIV. Adaptation in Vif has allowed cross-species transmission of SIV from monkeys to chimpanzees and
underlies the ancient origin of HIV-1. Accordingly, the APOBEC3-Vif interaction is an archetypical case of a
restriction factor and viral antagonist. In principle, host escape by mutation in APOBEC3 and viral adaptation in
Vif could occur through changes in protein binding interfaces, insertion of short-linear interaction motifs by
gene loss and overprinting or mutation of allosteric sites. However, there are no co-structures of Vif bound to
any APOBEC3 family member to document these phenomena, so the detailed mechanisms are unclear. In this
project, we will overlay sequencing and viral infectivity data accumulated at critical points during the
evolutionary history of HIV-1 with structures of corresponding Vif-A3 complexes. Cutting edge methods, such
as Fab-assisted single-particle cryo-EM, will be used to resolve these structures. The functional significance of
the observed interactions will be tested by mutagenesis in conjunction with viral infectivity assays in cells and
Vif ubiquitination activity assays in vitro. This project will provide a paradigmatic example of the biochemistry,
structure, and molecular mechanisms of molecular arms races that are general phenomena of host-pathogen
interactions.

## Key facts

- **NIH application ID:** 9993241
- **Project number:** 5P50AI150476-14
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** John D Gross
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $446,170
- **Award type:** 5
- **Project period:** 2007-08-27 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993241

## Citation

> US National Institutes of Health, RePORTER application 9993241, Structure and Evolution of APOBEC3-Vif Interactions (5P50AI150476-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9993241. Licensed CC0.

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