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Evolving understanding of HIV-1 reverse transcriptase structure, function, and inhibition.

Award Number: R01AI027690
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: 11/01/1988
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Evolving understanding of HIV-1 reverse transcriptase structure, function, and inhibition. - During the first 30 years of this grant, using X-ray crystallography, we have been able to describe the detailed molecular architecture of HIV-1 reverse transcriptase (RT) in complex with dsDNA, RNA/DNA, and dsRNA. These include structures poised for nucleotide incorporation, catalytic complexes, and post-incorporation structures prior to translocation. All of them represent key states for understanding the comprehensive nature of reverse transcription during HIV infection, and the mechanisms of action of and resistance to nucleoside RT inhibitor (NRTI) drugs. In a collaborative effort, our crystallographic structures enabled the discovery of two non-nucleoside RT (NNRTI) drugs (rilpivirine and etravirine), leading to five licensed anti-AIDS medications. During the previous grant period, major highlights included solving RT structures in complex with a dsRNA initiation complex prior to nucleotide incorporation, RT/DNA with an NNRTI, RT with NRTI drugs, and RT with nucleotide-competing RT inhibitors (NcRTIs) including INDOPY-1. We propose to follow up by determining a series of RT/DNA-RNA/RNA structures to map molecular details of how first-strand DNA synthesis is initiated, with a focus on conformational changes in RT and nucleic acid that accompany the transition from initiation (slow) to processive (fast) DNA synthesis. Similarly, details of second-strand initiation will be probed beginning with a structure of RT with the polypurine-tract RNA primer across from a DNA template. Additional HIV-1 RT structures with drugs and investigational inhibitors will be determined to further understand mechanisms of inhibition and resistance, and the potential for additional sites not currently targeted by anti-AIDS drugs. Although the HIV proteins and enzymes are produced initially as part of Gag-Pol precursor polyproteins, relatively little is known about the detailed structure and function of the immature forms prior to maturation. Recently, we have produced multiple-milligram amounts of the HIV-1 Gag-Pol and Pol precursor polyproteins for the first time. Cryo-EM determination of the HIV-1 Pol polyprotein shows a dimeric structure with RT in a p66/p51 heterodimer-like configuration at its core, suggesting that formation of the mature RT structure is guided from early stages of its morphogenesis. Formation of the RT dimeric core also brings the protease monomers into a dimeric arrangement, thus providing structural insight into the potential role of RT in protease activation during virion maturation. We will pursue further cryo-EM, crystallographic, and biophysical studies of the HIV-1 Pol polyprotein and its complexes with relevant binding partners to provide further structural and biophysical insights that shed light on various aspects of virus assembly and maturation. The proposed work relies on collaborations with Jeffrey DeStefano (Maryland), and Stephen Hughes (NCI- Frederick), Mamuka Kvaratskhelia (Colorado-Denver), Ronald Levy (Temple), Dmitry Lyumkis (Salk), Stefan Sarafianos (Emory), and Gilda Tachedjian (Monash).


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: 2024 ( Subtotal = $714,489 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	003	35	5/16/2024	NON-COMPETING CONTINUATION	$71,449
2024	2024	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	000	35	11/30/2023	NON-COMPETING CONTINUATION	$643,040
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	002	34	4/26/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$268,299
2024	2022	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	33	4/26/2024	NON-COMPETING CONTINUATION	-$268,299
														Subtotal = $714,489

Issue Date FY: 2023 ( Subtotal = $714,489 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	001	34	11/10/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$714,489
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	33	11/9/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $714,489

Issue Date FY: 2022 ( Subtotal = $714,489 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	33	11/23/2021	NON-COMPETING CONTINUATION	$714,489
														Subtotal = $714,489

Issue Date FY: 2021 ( Subtotal = $710,724 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	32	12/23/2020	NON-COMPETING CONTINUATION	$710,724
														Subtotal = $710,724

Issue Date FY: 2020 ( Subtotal = $709,970 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	31	12/11/2019	COMPETING CONTINUATION	$709,970
														Subtotal = $709,970

Issue Date FY: 2009 ( Subtotal = $872,498 )
2009	2009	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	001	21	9/7/2009	SUPPLEMENT FOR EXPANSION	$100,000
2009	2009	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	21	12/12/2008	COMPETING CONTINUATION	$772,498
														Subtotal = $872,498

Issue Date FY: 1998 ( Subtotal = $444,736 )
1998	1998	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Microbiology and Infectious Diseases Research	000	10	10/31/1997	NON-COMPETING CONTINUATION	$444,736
														Subtotal = $444,736

Grand Total All Awards = $4,881,395

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Evolving understanding of HIV-1 reverse transcriptase structure, function, and inhibition.

Award Number: R01AI027690

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: 11/01/1988

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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