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Role of the Viral Capsid in HIV-1 Integration

Award Number: R01AI136740
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: 07/15/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Role of the Viral Capsid in HIV-1 Integration - Abstract The goal of this proposal is to pinpoint the mechanism by which the HIV-1 capsid protein (CA) regulates viral DNA integration. HIV-1 CA is a multifunctional viral protein and is a new target for antiviral drug development. A first-in-class antiviral drug, lenacapavir, has been approved for the restricted treatment of multi-drug-resistant HIV-1 infection. Recently, a lenacapavir-based injectable has also been approved to prevent HIV-1 transmission. However, a CA-targeting front-line therapy for the treatment of all HIV-1 infections remains an unmet need. Development of a CA-based antiviral therapy requires a clear understanding of the mechanism by which CA promotes HIV-1 infection. HIV-1 CA regulates the early steps of reverse transcription and nuclear entry. In the previous funding cycle, we discovered that CA also regulates the integration step by controlling the preintegration complex (PIC) function. We reported that the replication defect of clinically relevant CA mutants was due to reduced integration. Additionally, our studies of PF74, a CA-inhibitor mapped the antiviral mechanism to a block at the integration step. The integration block was subsequently reported as part of the antiviral mechanism of lenacapavir. Collectively, these findings contributed significantly in pinpointing CA’s role during infection and in understanding the antiviral mechanism of CA inhibitors. In our continued efforts to clarify CA’s role, we have now generated new preliminary results suggesting that CA directly interacts with the nucleosome- the organizing unit of chromatin. Thus, in this renewal application we will test the hypothetical model that HIV-1 CA regulates integration by interacting with specific chromatin proteins. To study the novel interaction between HIV-1 CA and the nucleosome, we propose three Aims. Aim 1 will identify the determinants of HIV-1 CA and chromatin interaction. Aim 2 will test whether CA and nucleosome interaction promotes HIV-1 integration. Aim 3 will define the role of CA-binding host factors on CA-nucleosome interaction and the ensuing effect on integration. These studies clarifying the nuclear function of HIV-1 CA are timely, as the field is vigorously testing the new model that an intact, near intact or remodeled HIV-1 capsid enters the nucleus of an infected cell. Therefore, our studies to clarify CA’s role in HIV-1 infection will aid in the faster development of next- generation of CA-inhibitors. We are uniquely positioned for the proposed study, we are uniquely suited for this study, since we have- a) access to a unique set of reagents, b) developed a multipronged approach, and c) built a team that combines expertise in biochemistry (Dash), capsid (Aiken), chromatin biology (Karijolich), integration (Engelman), intasome (Craigie), retrovirus-chromatin interaction, (Goff), nucleosome assembly (Parissi), and primary cell biology (Hultquist). .


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 = $671,388 )
2026	2026	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Allergy and Infectious Diseases Research	001	5	9/3/2026	COMPETING CONTINUATION	$761,966
2026	2023	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	4	2/10/2026	NON-COMPETING CONTINUATION	-$90,578
														Subtotal = $671,388

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	4	7/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $370,000 )
2023	2023	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	4	7/19/2023	NON-COMPETING CONTINUATION	$370,000
														Subtotal = $370,000

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	3	7/15/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $370,000 )
2021	2021	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	3	6/23/2021	NON-COMPETING CONTINUATION	$370,000
														Subtotal = $370,000

Issue Date FY: 2020 ( Subtotal = $365,450 )
2020	2020	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	2	6/22/2020	NON-COMPETING CONTINUATION	$365,450
														Subtotal = $365,450

Issue Date FY: 2019 ( Subtotal = $376,825 )
2019	2019	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	1	7/15/2019	NEW	$376,825
														Subtotal = $376,825

Grand Total All Awards = $2,153,663

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Role of the Viral Capsid in HIV-1 Integration

Award Number: R01AI136740

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: 07/15/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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