# Regulation and Targeting of HIV-1 Integrase-RNA Interactions

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $466,500

## Abstract

Abstract
 The emergence of drug resistant human immunodeficiency virus type-1 (HIV-1) variants and the lack of
an effective vaccine require the development of novel anti-retroviral drugs. The catalytic activity of HIV-1
integrase (IN) has been successfully targeted by several highly effective and well tolerated IN strand transfer
inhibitors (INSTIs). However, despite high barriers with the second-generation INSTIs, mutations conferring
resistance to multiple INSTIs have been reported in clinical settings. Thus, targeting IN through an alternative
mechanism can complement the existing therapeutic strategies and substantially increase the barrier to
emergence of drug resistant HIV-1 variants upon INSTI treatment.
 IN has long been known to have an enigmatic non-catalytic function in the HIV-1 life cycle. Certain
mutations in IN, collectively referred to as class II mutations, are reportedly pleiotropic and result in defects in
viral particle assembly, maturation and reverse transcription. In a paradigm-shifting study, we have discovered
that HIV-1 IN binds to the viral RNA genome (gRNA) in virions and that this interaction is critically important for
accurate virion morphogenesis. Inhibition of IN-gRNA interactions through allosteric integrase inhibitors
(ALLINIs) or class II IN substitutions results in the formation of aberrant “eccentric” particles with the gRNA is
mislocalized between the empty capsid (CA) lattice and the viral envelope. Furthermore, we have shown that IN
tetramerization is critical for RNA-binding and that a number of class II IN substitutions located throughout IN
inhibit RNA binding through modulation of IN tetramerization. Finally, work from our lab demonstrated that
premature degradation of the gRNA and its physical separation from the reverse transcriptase enzyme in virions
underlies the reverse transcription defects of eccentric particles in target cells. Importantly, this untimely gRNA
degradation is not due to inhibition of IN-gRNA interactions per se, but rather due to loss of protection with the
CA lattice, as a similar outcome was observed upon CA destabilization. Together, these studies cemented the
role of IN-gRNA interactions in virion maturation and demonstrated the critical importance of the CA lattice in
protection of viral nucleic acids in target cells.
 Based on these novel findings and extensive preliminary data, we propose to elucidate the nature and
rules of HIV-1 IN-gRNA interactions, how IN binding to the gRNA mediates proper assembly of the HIV-1 capsid
lattice and how infected cells sense and respond to aberrant particles generated upon inhibition of IN-gRNA
interactions and destabilization of the CA lattice. These studies will fill a critical gap in our understanding of the
critical noncatalytic function of HIV-1 IN in particle maturation and the consequences of inhibiting these
interactions. Together, this project will not only enhance our basic knowledge of HIV-1 replication but also aid in
the deve...

## Key facts

- **NIH application ID:** 10738759
- **Project number:** 5R01AI150497-08
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Sebla B. Kutluay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $466,500
- **Award type:** 5
- **Project period:** 2017-01-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10738759

## Citation

> US National Institutes of Health, RePORTER application 10738759, Regulation and Targeting of HIV-1 Integrase-RNA Interactions (5R01AI150497-08). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10738759. Licensed CC0.

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