# The Cell Biology of HIV-1 Genome Trafficking

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $381,991

## Abstract

PROJECT SUMMARY / ABSTRACT
More than 36 million people worldwide are living with HIV-1 infection as of 2017, with HIV/AIDS causing
~1 million deaths per year. HIV-1 establishes a life-long, persistent infection. There are no therapies yet
capable of permanently suppressing viral gene expression in the context of acute infection or latency
rebound. This project’s long-term goal is to elucidate the cellular mechanisms that underpin HIV-1 RNA
subcellular trafficking, translation, and genome packaging toward the development of therapies to
selectively abrogate these stages in vivo. In the current funding period we elucidated cell-intrinsic barriers
to HIV-1 genome nuclear export in cells derived from mice and other rodents. We also developed cutting-
edge, quantitative imaging strategies for studying HIV-1 viral RNA (vRNA) trafficking and virus particle
assembly dynamics in human cells. Collectively, these studies revealed that cooperative interactions
between discrete cis-acting viral RNA structural elements and defined RNA binding proteins program
vRNAs for striking transport behaviors both in the nucleus and cytoplasm. For example, we found that HIV-
1’s Rev response element (RRE), regulated by the viral Rev protein and cellular XPO1 nuclear export
receptor, dictates a previously unanticipated 3-step vRNA transport pathway characterized by transient
subnuclear compartmentalization events, “burst” nuclear export kinetics, and diffusion to peripheral sites
of translation and genome packaging in the cytoplasm. Herein we test the overarching hypothesis that
HIV-1 is adapted to exploit XPO1-mediated “burst” export in order to ensure rapid, non-linear increases to
viral late stage gene expression and to promote the efficient delivery of viral genomes to virion assembly
sites at the cell periphery. The goal of Specific Aim 1 is to define the nuclear membrane events that
underpin XPO1-directed “burst” vRNA nuclear export using advanced high-resolution imaging modalities.
Specific Aim 2 applies a comparative visual and biochemical approach to define conserved features of
XPO1-linked vRNA export modules in the context of broad-spectrum antiviral targeting. Specific Aim 3
uses cell-based assays and new HIV-1 reporter viruses to study the links between “burst” export at the
nucleus and cytoplasmic events including Gag/Gag-Pol translation, genome packaging, and virus particle
assembly. Collectively, these detailed studies are intended to expose new cell biology, deliver innovative
tools for studying viruses, and identify novel virus-host interactions relevant to the development of
therapies to suppress HIV-1 virion production in vivo.

## Key facts

- **NIH application ID:** 10169228
- **Project number:** 5R01AI110221-08
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Nathan M Sherer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,991
- **Award type:** 5
- **Project period:** 2014-01-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169228

## Citation

> US National Institutes of Health, RePORTER application 10169228, The Cell Biology of HIV-1 Genome Trafficking (5R01AI110221-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10169228. Licensed CC0.

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