# Biochemical Mechanism of HIV DNA Integration

> **NIH NIH R37** · DANA-FARBER CANCER INST · 2024 · $679,163

## Abstract

PROJECT SUMMARY/ABSTRACT
HIV/AIDS remains a debilitating disease globally, with infections among young adults in the US in recent years
increasing. Although extensive efforts are dedicated to HIV vaccine and cure research, these approaches have
yet to yield candidates for routine clinical use. By contrast, combination antiretroviral therapy (cART) has been
used to reduce disease burden and mortality since its introduction into the clinic in the mid-1990s.
Recommended cART formulations contain an integrase inhibitor that inhibits the enzyme active site and its
strand transfer activity (integrase strand transfer inhibitor or INSTI). Despite their resounding success,
incidence of resistance to second-generation INSTIs is increasing, and will predictably increase further as
these drugs are rolled out for global usage. Paralleling the success of active site and allosteric site inhibitors of
the reverse transcriptase enzyme, the clinic will benefit greatly from the addition of a second class of integrase
inhibitor, such as allosteric integrase inhibitors (ALLINIs). This grant over the current funding cycle made
seminal contributions to understanding the mechanism of action of pre-clinical ALLINI compounds, and such
compounds are today in development at pharmaceutical companies. In this grant application we will continue
to categorize the mechanism of ALLINI action, which is critical basic information required in advance of clinical
rollout and clinical drug resistance. This research will in part be focused on the mechanism of action of the
integrase binding protein lens epithelium-derived growth factor (LEDGF)/p75, which helps to guide the virus to
active genes for integration. In particular, some of the best-studied ALLINI chemotypes are effective inhibitors
of the LEDGF/p75-integrase binding interaction. Inspired by the success of LEDGF/75 binding site ALLINI
compounds, we will now characterize in detail interactions of additional host factors that are shown to bind
integrase. As evidenced by the large variety of mutations that cause pleiotropic replication catastrophe, HIV-1
integrase is extremely sensitive to change. Characterization of novel host factor-integrase complexes will
define new targets for future antiretroviral inhibitor development.

## Key facts

- **NIH application ID:** 10845292
- **Project number:** 5R37AI039394-29
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Alan N. Engelman
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $679,163
- **Award type:** 5
- **Project period:** 1996-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845292

## Citation

> US National Institutes of Health, RePORTER application 10845292, Biochemical Mechanism of HIV DNA Integration (5R37AI039394-29). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10845292. Licensed CC0.

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