# Investigating the integration-independent role of HIV-1 integrase in the viral life cycle and virion morphogenesis

> **NIH NIH F31** · WASHINGTON UNIVERSITY · 2020 · $6,273

## Abstract

Project Summary
Anti-retroviral drugs have transformed HIV-1 infection from a death sentence to a chronic illness, but the rate
with which HIV-1 evolves to acquire drug-resistance mandates constant research and development of new
antiretroviral compounds. The HIV-1 integrase (IN) enzyme is a dynamic protein that plays a vital role in the
HIV-1 lifecycle, and is the target of some of the most widely used, clinically approved antiretroviral drugs. The
long-standing view that integration is the sole role of IN was challenged when a recent study surprisingly found
that in addition to binding proviral DNA in target cells, IN also binds viral genomic RNA in virions. Intriguingly,
inhibition of IN-RNA interactions through mutations within the C-terminal domain (CTD) or by allosteric
integrase inhibitors (ALLINIs) results in mislocalization of the viral genomic RNA outside the capsid lattice in
virions. These findings demonstrate that IN is essential during virion maturation, and this function may also be
a druggable target. However, it is unknown how IN ensures proper placement of viral RNA within virions. While
ALLINIs are proposed to inhibit IN-RNA interactions indirectly by inducing aberrant IN multimerization, CTD
mutations are shown to directly inhibit IN binding to viral RNAs without affecting its multimeric state. As such, it
is currently unclear whether IN multimerization or IN-RNA interactions drive proper particle maturation. IN-RNA
interactions alone cannot adequately explain why IN is important for virion morphogenesis, as there are many
Class II IN mutations scattered along the length of the IN protein which cause the same phenotype without
changing the residues that directly bind RNA. I hypothesize that IN takes on a specific multimeric state or
states during virion maturation which allows its binding to the viral genomic RNA. Here, I propose to
characterize a panel of 25 distinct mutant IN viruses that are reported to have defects in replication and/or
virion morphology or are predicted to affect IN multimerization (Aim 1). Using these mutants and employing
biochemical approaches, I propose to determine whether IN multimerization or IN-RNA interactions drive virion
morphogenesis (Aim 2). Finally, I plan to determine when during particle genesis IN binds to RNAs and why
these eccentric particles are noninfectious (Aim 3). A better understanding of how IN contributes to proper
virion maturation would greatly aid the development of new antiretroviral compounds that target a novel
function of this essential enzyme.

## Key facts

- **NIH application ID:** 10003809
- **Project number:** 5F31AI143389-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** JENNIFER L ELLIOTT
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $6,273
- **Award type:** 5
- **Project period:** 2019-09-01 → 2020-10-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003809

## Citation

> US National Institutes of Health, RePORTER application 10003809, Investigating the integration-independent role of HIV-1 integrase in the viral life cycle and virion morphogenesis (5F31AI143389-02). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10003809. Licensed CC0.

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