# REGULATION AND TARGETING OF HIV-1 INTEGRASE-RNA INTERACTIONS

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $301,188

## Abstract

Abstract
 Based on mutational studies two decades ago, HIV-1 Integrase (IN) protein has been proposed to play a
role in late stages of HIV-1 replication. These mutations, collectively referred to as Class II mutations,
adversely affect multiple steps of virus replication including particle assembly, maturation and subsequent
reverse transcription. Some class II mutations specifically impair particle maturation leading to the formation of
aberrant viral cores in which the viral ribonucleoprotein complexes (RNPs) are mislocalized outside of the
conical capsid core. However, for nearly 20 years it has remained enigmatic as to how IN can contribute to
proper viral particle maturation.
 Allosteric IN inhibitors (ALLINIs) have recently emerged as a promising new class of antiretroviral agents
and select compounds are currently in clinical trials. Although ALLINIs were initially designed to block the
interaction of IN with its cellular cofactor LEDGF/p75, it has recently been shown that they potently impair the
late steps of HIV-1 replication. Similar to certain Class II IN mutations, these inhibitors selectively interfere with
proper virus particle maturation and yield non-infectious particles with eccentrically positioned RNPs. Although
it has been shown that ALLINIs can promote aberrant IN multimerization, how this event adversely results in
the mislocalization of the RNPs outside the capsid core has remained unknown.
Based on these observations, we have recently explored the
intriguing possibility that IN may bind the viral
RNA genome in mature particles and that ALLINIs may interfere with IN-RNA interactions critical for proper
particle formation.
To test this hypothesis, we have employed the cutting-edge CLIP-seq (crosslinking-
immunoprecipitation-sequencing) methodology and complementary biochemical approaches. These studies
have revealed for the first time that IN binds to specific sequences on the viral RNA genome and that certain
mutations within IN and ALLINIs potently block these interactions. We propose to continue our studies in
identifying the details of the mechanism by which ALLINIs affect IN-RNA interactions and how IN-RNA
interactions regulate particle maturation. We also propose to use the aberrantly formed eccentric cores
generated in the presence of ALLINIs/Class II mutations as a tool to understand the early post-entry events in
infection. As such, this project will not only provide unprecedented insight into the novel role of HIV-1 IN in
particle assembly and the primary mechanism of action of ALLINIs, but will also facilitate the development of
studies to understand early post-entry events in HIV-1 replication.

## Key facts

- **NIH application ID:** 9828559
- **Project number:** 8R01AI150497-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Sebla B. Kutluay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $301,188
- **Award type:** 8
- **Project period:** 2017-01-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828559

## Citation

> US National Institutes of Health, RePORTER application 9828559, REGULATION AND TARGETING OF HIV-1 INTEGRASE-RNA INTERACTIONS (8R01AI150497-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828559. Licensed CC0.

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