# Exploiting Natural Post-Integration Barriers to Restrict HIV-1 Replication

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $203,222

## Abstract

PROJECT SUMMARY/ABSTRACT
The Berlin patient demonstrates that cure of HIV is possible, and the likely mechanism of cure
(transplantation with CCR5∆32 cells) suggests that cell-intrinsic resistance represents a potential
therapeutic scenario for a full or functional cure for HIV/AIDS. For several years, we have studied natural,
cell-intrinsic barriers to HIV-1 gene expression in cells derived from mice and other rodents. Two of these
barriers map to genes encoding host proteins Cyclin T1 (CCNT1) and Exportin-1 (XPO1, also known as
CRM1) that are essential regulators of HIV-1 gene expression and latency reversal. In human cells, CCNT1
interacts with the viral Tat protein to promote HIV transcriptional elongation, while XPO1 is bound by the
viral Rev protein to mediate nuclear export of intron-containing viral mRNAs and the viral RNA genome. In
mouse cells, Tat-Ccnt1 and Rev-Xpo1 interactions are inefficient due to species-specific differences
between mouse and human orthologues of either protein. Why these highly conserved genes evolved
differences in the rodent and primate lineages is unknown, and the rise of CRISPR/Cas9 technology
provides us with the unprecedented opportunity to test the hypothesis that knocking-in mouse-specific
features of CCNT1 and XPO1 into human T cells will suppress HIV-1 replication in vitro and in vivo with
little net impact on host cellular biology. Indeed, our project is premised on exciting preliminary data
showing that modifying a single species-specific codon of human CCNT1 in a human T cell line is sufficient
to abolish HIV-1 Tat activity and viral replication, with no discernable effects on cell proliferation. Herein
we request support for collaborative studies between the Sherer and Kumar labs to further our studies of
mouse-informed CCNT1 and XPO1 gene modifications in human T cells, and to determine the potential of
targeting these genes as a resistance/treatment strategy for HIV-1.

## Key facts

- **NIH application ID:** 9827529
- **Project number:** 5R21AI143800-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Priti Kumar
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $203,222
- **Award type:** 5
- **Project period:** 2018-11-21 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9827529

## Citation

> US National Institutes of Health, RePORTER application 9827529, Exploiting Natural Post-Integration Barriers to Restrict HIV-1 Replication (5R21AI143800-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9827529. Licensed CC0.

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