# Role of Apobecs in Retroviral Immunity

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2021 · $452,755

## Abstract

Project Summary
 Innate immunity requires cellular restriction factors that inhibit the replication of multiple pathogens.
One group of restriction factors is the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like
(Apobec) family of cytosine deaminases, including activation-induced cytosine deaminase (AID). AID
function includes both innate and adaptive immune responses due to its role in control of retrotransposons
as well as somatic hypermutation of immunoglobulin variable regions and class switch recombination.
Apobec family enzymes are known inhibitors of complex human retroviruses, such as the lentivirus human
immunodeficiency virus (HIV-1), as well as DNA-containing viruses. HIV-1 encodes an Apobec antagonist,
Vif and, in the absence of Vif, the provirus sustains high numbers of G to A hypermutations due to cytosine
deamination on the minus strand during reverse transcription. My laboratory has shown that mouse
mammary tumor virus (MMTV) is the only known complex mouse retrovirus with organizational and
functional features similar to HIV, such as the regulatory protein Rem. Rem is a precursor protein that is
cleaved by signal peptidase at the ER membrane to give an N-terminal signal peptide (SP) that has Rev-like
function and a C-terminal protein of unknown function. Inoculation of cloned MMTV lacking Rem
expression into BALB/c mice resulted in mammary tumors with a decreased incidence and latency
compared to wild-type MMTV. Characterization of MMTV proviruses from these mammary tumors showed
extensive G to A as well as other transition mutations on both DNA strands, consistent with AID-type
mutations, but also some typical of the consensus sequences and strand specificity of murine Apobec3
(mA3) or other deaminases. Transfection experiments revealed proteasomal degradation of AID in the
presence of Rem, but not mA3. These results led us to the hypothesis that Rem is an HIV-1 Vif-like
antagonist of multiple Apobec cytosine deaminases. This application will test several aspects of this
hypothesis. In Aim 1, we will determine sequences within Rem and AID that are necessary for proteasomal
degradation. We will identify the E3 ligase for AID protein interactions in the presence and absence of Rem
using screens that detect biotinylation of interacting proteins by BirA or conjugation to an AID-ubiquitin
fusion protein. The role of Rem retrotranslocation for AID degradation will be investigated. In Aim 2,
MMTVs or T-cell variants lacking Rem expression will be used to determine the types of transition mutations
observed in proviruses after infections of knockout mice lacking one or more Apobec genes. These studies
will use a complex mouse retrovirus to explore aspects of innate immunity that are difficult to test in vivo
with human viruses. Our experiments will provide improved understanding of Apobec function as well as
potential application to the treatment of human infectious diseases and cancers.

## Key facts

- **NIH application ID:** 10220683
- **Project number:** 5R01AI131660-05
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Jaquelin Page Dudley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $452,755
- **Award type:** 5
- **Project period:** 2017-09-25 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220683

## Citation

> US National Institutes of Health, RePORTER application 10220683, Role of Apobecs in Retroviral Immunity (5R01AI131660-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10220683. Licensed CC0.

---

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