# Structural determinants for integrase pleiotropism in viral maturation

> **NIH NIH U54** · SEATTLE CHILDREN'S HOSPITAL · 2021 · $319,681

## Abstract

Abstract
The studies in Project 1 will center on elucidating structural determinants for a second, non-catalytic function of
HIV-1 integrase (IN) during virion maturation. While an essential role of IN for integration of viral cDNA into
human chromosome during early steps of HIV-1 infection has been long established and successfully exploited
as a therapeutic target, the recent studies with allosteric IN inhibitors (ALLINIs) by HIVE investigators coupled
with earlier site-directed mutagenesis experiments have suggested that IN plays an active role in viral particle
maturation. During the past funding period our studies with ALLINIs, a new class of very promising antiviral
compounds, which are currently in clinical trials, have uncovered that these inhibitors induce hyper or aberrant
multimerization of HIV-1 IN and yield eccentric, non-infectious virions where the ribonucleoprotein complexes
(RNPs) are mislocalized outside of the translucent capsid cores. Subsequent collaborative efforts by HIVE and
CRNA investigators have revealed that IN binds the viral RNA genome to ensure correct localization of RNPs
within the protective capsid core, whereas ALLINI treatments impair IN-RNA interactions and result in the
eccentric core phenotype. These seminal findings will now be extended to elucidate key structural interactions
that underlie these biological events. In particular, our experiments will take advantage of cutting-edge
technologies available within the HIVE center as well as utilize complementary expertise of CRNA and PCHPI
scientists to accomplish the following aims. Aim 1 will determine the cryo-EM structure of IN bound to a cognate
RNA element; aim 2 will dissect complementary interactions of IN and nucleocapsid with viral RNA using single
molecule fluorescence and SHAPE; aim 3 will examine the significance of IN-RNA interactions in non-primate
lentiviruses and other retroviruses using CLIP-seq and biochemical approaches; aim 4 will investigate the
structural basis for ALLINI induced hyper-multimerization of full length wild type IN using solid state NMR and
free energy calculations; and aim 5 will generate mesoscale models of correctly matured and ALLINI treated
eccentric virus particles. These highly innovative experiments will push the boundaries of rapidly developing
technologies such as single particle cryo-EM, solid-state NMR and computational modeling as well as critically
advance our understanding of molecular events that shape the formation of infectious virions.

## Key facts

- **NIH application ID:** 10242905
- **Project number:** 5U54AI150472-11
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Mamuka Kvaratskhelia
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $319,681
- **Award type:** 5
- **Project period:** 2012-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242905

## Citation

> US National Institutes of Health, RePORTER application 10242905, Structural determinants for integrase pleiotropism in viral maturation (5U54AI150472-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10242905. Licensed CC0.

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