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Spatiotemporal Staging of the HIV-1 Preintegration complex

Award Number: R01AI170228
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: 05/20/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Spatiotemporal Staging of the HIV-1 Preintegration complex - ABSTRACT Approximately 1.2 million people in the US and ~40 million people worldwide are infected with HIV. In spite of significant progress in HIV/AIDS research, anti-retroviral therapy (ART) remains the only treatment option available for HIV-1 infection. ART has been highly effective in controlling the virus and making HIV infection a manageable disease. Specifically, inhibitors of HIV-1 Integrase (IN) are used as the preferred drugs in the current ART regimens. However, these inhibitors continue to face drug resistance and there is growing concern of the adverse metabolic and neuropsychiatric effects of these inhibitors. Thus, there is a need for the development of new and improved IN inhibitors for effective and long-term control HIV-1 infection. Such effort is critically dependent on a better understanding of the mechanisms of HIV-1 integration. It is important to note that studies of the preintegration complex (PIC) extracted from acutely infected cells have been instrumental in defining the mechanisms of HIV-1 integration. Furthermore, PIC studies have played a central role in the development of currently used IN inhibitors. Therefore, our proposal to define the mechanism of HIV-1 PIC formation will generate new knowledge to promote the development of new and improved IN-based therapies. Retroviral replication is dependent on the essential steps of reverse transcription (RTN) and integration. In the case of HIV, the RNA genome is reverse transcribed into a DNA copy by the reverse transcription complex (RTC). Then, the RTC transitions into a PIC by an unknown mechanism and undefined time. The PIC, containing the viral DNA, the IN enzyme, and other viral/host factors, carries out integration. The prevailing view is that HIV-1 RTN is completed in the cytoplasm and/or at the nuclear pore complex (NPC). Thus, nuclear entry of the PIC is necessary to carry out HIV-1 DNA integration into the host chromosomes. However, new evidence suggest that the intact HIV-1 capsid enters the nucleus and RTN is completed after the nuclear entry step. A nuclear completion of RTN creates key knowledge gaps in our current understanding of the PIC. We hypothesize that functional HIV-1 PICs are formed prior to the completion of RTN and nuclear entry protects the integrity of the PIC-viral DNA. This proposal will test this hypothesis through three specific aims: Aim 1 will define the link between the timing of functional PIC formation relative to RTN completion, Aim 2 will assess the role of nuclear entry on PIC function, and Aim 3 will determine the spatiotemporal transition of the RTC to a PIC. For these aims, we have developed a novel approach of quantifying PIC-specific integration activity and measuring HIV-1 core-mediated DNA integration, coupled with the blockade of viral nuclear entry and time of inhibitor addition assays. Together, these studies will define the mechanistic and kinetic link between HIV-1 RTN and PIC function. Most importantly, our team is uniquely qualified to successfully complete this timely R01-project, since we have the expertise, reagents, and the tools required to study PIC biochemistry (Dash), Capsid biology (Aiken), Nuclear entry (Campbell), and Integration (Engelman and Craigie).


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: 2025 ( Subtotal = $695,444 )
2025	2025	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	3	5/23/2025	NON-COMPETING CONTINUATION	$695,444
														Subtotal = $695,444

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	2	5/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $805,630 )
2023	2023	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	2	4/6/2023	NON-COMPETING CONTINUATION	$650,630
2023	2023	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Allergy and Infectious Diseases Research	001	2	8/3/2023	NON-COMPETING CONTINUATION	$155,000
														Subtotal = $805,630

Issue Date FY: 2022 ( Subtotal = $658,830 )
2022	2022	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	1	5/20/2022	NEW	$658,830
														Subtotal = $658,830

Grand Total All Awards = $2,159,904

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Spatiotemporal Staging of the HIV-1 Preintegration complex

Award Number: R01AI170228

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: 05/20/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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