# Interplay between reverse transcription and host restriction

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $518,433

## 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 (A3) 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. Sensor binding 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 A3. These host anti-viral events are believed to occur
largely in the cytoplasm, where A3 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 used A3 and nucleic acid sensor knockout (KO) mice and genetically engineered
animals that express human A3 proteins in these studies. Our data, based on our analysis of A3 KO mice and
cells, suggest that the initial step occurs in the cytoplasm but that reverse transcription may also occur 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 dete...

## Key facts

- **NIH application ID:** 10867275
- **Project number:** 5R01AI174538-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** SUSAN R ROSS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $518,433
- **Award type:** 5
- **Project period:** 2023-06-14 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867275

## Citation

> US National Institutes of Health, RePORTER application 10867275, Interplay between reverse transcription and host restriction (5R01AI174538-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10867275. Licensed CC0.

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