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Structural and Biochemical Effects of Capsid-targeting Molecules on HIV-1 Capsid Assembly

Award Number: F31AI174951
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/29/2022
PERIOD OF PERFORMANCE END DATE: 12/28/2026

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Structural and Biochemical Effects of Capsid-targeting Molecules on HIV-1 Capsid Assembly - Abstract HIV infection impacts over 37 million individuals, with over 2/3 of these patients receiving antiretroviral therapies (ART). ART is sustained for a patient’s life and can lead to the emergence of drug-resistant HIV-1. To combat drug-resistance, an improved and diverse set of antiretrovirals are needed for clinical use. To this extent, the HIV-1 capsid is an excellent target for antiretroviral therapies as it has numerous, essential roles throughout the HIV-1 replication cycle. Compounds that target the capsid protein (CA), known as capsid effectors (CEs), offer a novel class of HIV-1 antivirals for potential clinical use. One CE with marked success is lenacapavir, developed by Gilead Sciences. Lenacapavir is exceptionally potent, however, early results show treatment with lenacapavir can cause the emergence of antiviral-resistant HIV-1. Our lab has previously reported highly potent antiretrovirals that target the same site as lenacapavir, within the FG-binding pocket. Compounds that bind to the FG-binding pocket of CA mimic a conserved phenylalanine-glycine (FG) dipeptide motif found in many host factors reported to bind CA. Here, I will characterize structural changes to the HIV-1 capsid upon treatment with highly potent CEs that bind the FG-binding pocket and calculate the biochemical parameters of CA•CE interactions for this class of antiretroviral therapeutics. The nature of CA•CE interactions will be assessed in wild-type (WT) and drug-resistant viruses to further our understanding of antiviral resistance. Electron microscopy (EM) will be used to visualize drug-resistant capsid assemblies and discern structural changes relative to WT assemblies (AIM 1). Rates of capsid assembly and changes to thermal stability upon drug-treatment will be calculated using assays designed to probe CA•CA interactions (AIM 2). These aims will study mutations that confer antiviral-resistance and results will be compared to WT CA to identify those with similar phenotypes and therefore higher risks of resistance. Further, CA•CE biochemical parameters of affinity and dissociation rates will be solved by label-free optical detection. This study will further our mechanistic understanding of compounds that bind to the FG-binding pocket of CA. Overall, these results will enable future research to strategically improve antiretrovirals, aiming to combat the HIV-1 epidemic.


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 = $49,538 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	4	12/4/2025	NON-COMPETING CONTINUATION	$49,538
														Subtotal = $49,538

Issue Date FY: 2025 ( Subtotal = $49,538 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	3	7/31/2025	NON-COMPETING CONTINUATION	$564
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	3	11/21/2024	NON-COMPETING CONTINUATION	$48,974
														Subtotal = $49,538

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	2	12/6/2023	NON-COMPETING CONTINUATION	$47,694
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	2	5/8/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $48,974

Issue Date FY: 2023 ( Subtotal = $47,694 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	1	12/16/2022	NEW	$0
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	1	12/5/2022	NEW	$46,752
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	002	1	12/29/2022	NEW	$0
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	003	1	2/24/2023	NEW	$942
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	004	1	2/24/2023	NEW	$0
														Subtotal = $47,694

Grand Total All Awards = $195,744

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Structural and Biochemical Effects of Capsid-targeting Molecules on HIV-1 Capsid Assembly

Award Number: F31AI174951

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/29/2022

PERIOD OF PERFORMANCE END DATE: 12/28/2026

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