# Structural basis for activity of and resistance to HIV integrase inhibitors

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2020 · $671,733

## Abstract

Abstract
The Human Immunodeficiency Virus Type 1 (HIV-1, hereafter referred to as HIV) currently infects ~37 million
people worldwide, and the number of infected individuals continues to rise. In the absence of a cure, antiretroviral
therapy (ART) represents the primary treatment option, as it slows disease progression, and limits new infections.
Integrase (IN) Strand Transfer Inhibitors (INSTIs) are a class of ART that block integration of viral DNA into host
chromosomes, a process that is mediated by the viral IN enzyme, which assembles into oligomeric nucleoprotein
complexes on the ends of viral DNA, termed “intasomes”. INSTIs selectively target intasomes and represent
first-line therapies in the clinic. However, the emergence of IN variants resistant to INSTIs is a major clinical
problem. Structural biology approaches can decipher the molecular mechanisms underlying drug action and
resistance, providing useful information for rationally improving current therapies. In this proposal, approaches
centered around revolutionary advances in cryo-electron microscopy for structural studies will be used to
understand how INSTIs interact with their natural drug target, the HIV intasome, as well as mechanisms by which
resistance to these drugs emerges.
 The proposed aims will address several major themes. Aim 1 will define the mechanisms of action of clinical
and developmental INSTIs in the context of HIV intasomes. Procedures used to perform high-resolution
structural studies of INSTI-bound complexes by cryo-EM will then be adopted to decipher novel, clinically
relevant mechanisms of drug resistance that arise in response to INSTI treatment. This work will be
complemented using biochemical and virology assays designed to dissect key interactions between HIV
intasomes and INSTIs and to validate structural findings. Aim 2 will extend these findings to define INSTI
mechanism of action in the presence of biologically relevant cellular factors, including methylated
mononucleosomes (mMNs; the natural target for HIV integration) and lens epithelium-derived growth factor
(LEDGF). Aim 2 will therefore define the biochemical and structural mechanisms by which INSTIs interact with
and inhibit IN catalytic activity in the context of the intasome-LEDGF-mMN complex, thereby elucidating how
INSTIs function in infected cells and their precise stage of activity.
 In addition to providing the first structural information for INSTI interactions with their natural drug target in
the presence of relevant cellular factors, this work will: 1) elucidate how mutations within the IN active site disrupt
drug binding, 2) define the precise stage and mechanism of action of this important class of drugs in a cellular
context, and 3) provide blueprints for the rational improvement of future INSTIs.
!

## Key facts

- **NIH application ID:** 9988158
- **Project number:** 5R01AI136680-04
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Dmitry Lyumkis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $671,733
- **Award type:** 5
- **Project period:** 2017-09-25 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988158

## Citation

> US National Institutes of Health, RePORTER application 9988158, Structural basis for activity of and resistance to HIV integrase inhibitors (5R01AI136680-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9988158. Licensed CC0.

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