# Role of APOBEC3 in in vivo Restriction of Retrovirus Infection

> **NIH NIH R56** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2022 · $479,700

## Abstract

Infectious agents have infected prokaryotes and eukaryotes throughout evolution. Indeed, there is co-evolution
of organisms and their infectious agents, with development of protective responses in the hosts and adaptive
countermeasures by the infectious agents. Infectious endemic retroviruses like murine leukemia virus (MLV)
have existed in mice for millions of years and provide us with an outstanding model system to understand how
mammalian hosts suppress virus replication and conversely, how viruses counteract this restriction. One system
of viral restriction is conferred by the apolipoprotein B mRNA editing enzyme, catalytic peptide 3 (APOBEC3)
family of proteins, which are packaged into retroviruses in virion-producing cells and after infection of target cells,
either block reverse transcription or deaminate deoxycytidine residues in single-stranded DNA, resulting in
uracils and G-to-A mutations in the viral genome. The products of retrovirus reverse transcription (ssRNA, ssDNA
and dsDNA) are also sensed by host nucleic acid sensors. Binding of these sensors to viral nucleic acid leads
to the production of anti-viral cytokines and chemokines, such as type I interferons, which “warns” surrounding
cells to arm themselves against infection by producing proteins such as APOBEC3. These host anti-viral events
are believed to occur largely in the cytoplasm, where APOBEC3 proteins and many host sensors are believed
to function.
 Retroviruses enter cells when the viral and host membranes fuse and capsids are deposited in the
cytoplasm. Reverse transcription initiates from within the capsid and capsid dissociation and reverse
transcription are mutually dependent; because DNA is more rigid than RNA, without capsid dissociation, reverse
transcription cannot proceed and conversely, the generation of DNA facilitates capsid dissociation. The reverse
transcription complex not only consists of viral RNA, DNA and the viral proteins reverse transcriptase and
integrase, but viral capsid and other proteins such as the MLV protein p12, which is needed for tethering of the
proviral DNA to host chromatin to achieve integration.
 Recently, there has been much debate as to whether reverse transcription occurs solely in the cytoplasm or
in the nucleus or both. Our lab pioneered the use of in vivo mouse models to study how A3 proteins restrict
retrovirus infection and has developed A3 knockout mice and genetically engineered animals that express
human A3 proteins. Our data, based on our analysis of A3 KO mice and cells, strongly suggest that the initial
steps of reverse transcription occurs in the cytoplasm. With these mouse models, we have the tools to carry out
in vitro, ex vivo and in vivo studies to determine how A3-mediated restriction and sensing of reverse transcripts
are integrated with reverse transcription and nuclear entry for MLV and its natural host, the mouse. To
accomplish this, we propose 3 aims, that will determine: I. Where in the cells APOBEC3 protein...

## Key facts

- **NIH application ID:** 10606970
- **Project number:** 2R56AI085015-12A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** SUSAN R ROSS
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $479,700
- **Award type:** 2
- **Project period:** 2010-02-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10606970

## Citation

> US National Institutes of Health, RePORTER application 10606970, Role of APOBEC3 in in vivo Restriction of Retrovirus Infection (2R56AI085015-12A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10606970. Licensed CC0.

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