Saturday, December 27, 2025 12/27/2025

Structural basis for activity of and resistance to HIV integrase inhibitors

Award Number: U01AI136680
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/25/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2025

Group Awards By:

View Award Description

Structural basis for activity of and resistance to HIV integrase inhibitors - ABSTRACT The Human Immunodeficiency Virus Type 1 (HIV-1, hereafter referred to as HIV) currently infects ~40 million people worldwide, and the number of infected individuals continues to rise. In the absence of a cure, antiretroviral therapy represents the primary treatment option, because it slows disease progression and reduces new infections. Integrase (IN) Strand Transfer Inhibitors (INSTIs) are a class of antiretroviral therapeutics 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 becoming a greater clinical problem. Structural biology approaches can shed light on the mechanisms underlying drug action and resistance, providing useful information for rationally improving the current INSTIs. When complemented with ancillary techniques, such as biochemical activity assays, biophysical thermodynamic and kinetic measurements, cellular virology, and diverse computational approaches including free energy calculations, the structures precisely detail mechanisms of resistance against specific INSTIs and provide guidance for designing and developing novel 3rd generation INSTIs to fight infections. In this proposal, approaches centered around using revolutionary advances in cryo-electron microscopy for structural studies will show how INSTIs interact with their natural drug target, the HIV intasome (both WT and mutant), and elucidate the mechanisms by which resistance to these drugs emerges. There are three Specific Aims that will: (1) extend and build upon current efforts to provide a mechanistic understanding of both why and how select viral resistant variants (VRVs) arise in response to the clinically used drug Dolutegravir (DTG) or the most potent developmental in-house compound that 4d, which is currently under pre-clinical evaluation; (2) broadly identify and analyze novel mechanisms and pathways of drug resistance that arise in response to treatment with 2nd generation drugs, highlighting both primary and compensatory mutations, and providing strategies to predict future variants; (3) select for residual resistant variants arising in response to treatment with novel 3rd generation INSTIs that were synthesized based on the concept of substrate mimicry, many of which effectively inhibit viral resistant variants that arise in response to treatment with 2nd generation clinically used INSTI drugs, and explain mechanisms underlying the superior potency of novel compounds. This work will improve our understanding of an important class of drugs used to treat people living with HIV, identify mechanisms, pathways, and patterns of clinically relevant resistance to INSTIs, and provide specific guidelines for their rational improvement.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	8	12/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $1,343,802 )
2025	2025	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	9	9/2/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,343,802
2025	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	8	9/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,343,802

Issue Date FY: 2024 ( Subtotal = $671,901 )
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	8	8/2/2024	NON-COMPETING CONTINUATION	$671,901
														Subtotal = $671,901

Issue Date FY: 2023 ( Subtotal = $703,450 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	7	8/1/2023	NON-COMPETING CONTINUATION	$671,901
2023	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	6	3/9/2023	COMPETING CONTINUATION	$31,549
														Subtotal = $703,450

Issue Date FY: 2022 ( Subtotal = $686,511 )
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	6	7/6/2022	COMPETING CONTINUATION	$686,511
														Subtotal = $686,511

Grand Total All Awards = $3,405,664

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Structural basis for activity of and resistance to HIV integrase inhibitors

Award Number: U01AI136680

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/25/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer