Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Molecular Pathways Leading to Drug Resistance in HIV-1 Integrase

Award Number: R21AI197945
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/10/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2028

Group Awards By:

View Award Description

Molecular Pathways Leading to Drug Resistance in HIV-1 Integrase - ABSTRACT There are ~40 million people world-wide infected by the Human Immunodeficiency Virus (HIV). In the absence of a functional cure, antiretroviral therapy (ART) represents the primary treatment option against HIV. ART regimens containing the integrase strand transfer inhibitors (INSTIs) form first-line treatments for people living with HIV/AIDS (PLWH). INSTIs work by blocking the function of the viral intasome, which is the nucleoprotein complex that forms on the linear ends of the viral long-terminal repeats and mediates the insertion of viral DNA into host target DNA. Despite significant advances afforded by the inclusion of INSTIs to ART regimens, resistance to even the latest drugs is becoming a greater clinical problem. In the clinical literature, there are specific sets of drug-resistant mutations (DRMs) within the IN protein that arise most frequently to INSTI therapy, including individual mutations E138K, G140A/S, and Q148H/K/R. Eventually, the virus evolves more complex combinations of mutations, including the clinically relevant triple mutants E138K/G140A/Q148K (KAK) and E138K/G140S/Q148H (KSH). In preliminary data, models of HIV fitness landscapes built from viral sequences derived from PLWH suggest that the pathways through which combinations of complex triple mutant KAK and KSH combinations emerge can vary dramatically. However, the underlying basis for how and why distinct DRM combinations preferentially emerge remains unclear. This work will test the fundamental hypothesis that the pathways toward drug resistance evolution can be rationalized using atomic resolution structures, supported by multiple experimental measures of viral fitness. In three specific aims, this work will (i) derive drug- specific pathway orderings for KAK and KSH combinations using tools that measure prevalence-based fitness based on extensive viral sequencing data available from PLWH, (ii) determine atomic structures of HIV intasomes along KAK and KSH pathways using the latest technological advances in cryogenic electron microscopy, and (iii) gain dynamic and mechanistic insights into select DRMs along KAK and KSH pathways. Collectively, the structural snapshots will be ordered along the predicted pathway trajectories and, together with existing fitness measurements and complementary molecular dynamics-based analyses, will begin to rationalize the pathways of drug resistance evolution, as well as the associated mechanisms of drug resistance to INSTI therapy. Although the mechanistic analyses of drug resistance have been interrogated in the past, considerably less attention has been given to understanding pathways of drug resistance evolution. Dissecting both pathways and mechanisms of patient-derived clinically relevant complex DRM combinations that arise in response to treatment will build a foundation for prospectively forecasting the evolutionary trajectories leading to drug resistance. The principles can be extended to other infectious diseases, beyond HIV.


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 = $515,625 )
2026	2026	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	1	2/10/2026	NEW	$515,625
														Subtotal = $515,625

Grand Total All Awards = $515,625

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Molecular Pathways Leading to Drug Resistance in HIV-1 Integrase

Award Number: R21AI197945

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/10/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer