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Structural Biophysics of HIV Splicing and Transcriptional Control

Award Number: R01AI150830
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: 08/19/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Structural Biophysics of HIV Splicing and Transcriptional Control - Project abstract: Despite advances in antiretroviral therapy, HIV continues to pose serious threats to human health and global economies. Knowledge gaps in understanding the basic mechanisms that control HIV gene expression present critical barriers to identifying novel targets for therapeutic intervention or strategies to coun- teract viral latency. In this proposal, we endeavor to close those gaps concerning the contributions of RNA struc- tural dynamics to HIV splicing and transcriptional control. We posit that HIV uses structured RNA elements to direct the cooperative assembly of specific RNA-protein (RNP) complexes that in turn modulates splicing. This type of RNA-mediated cooperativity is an innovative concept that explains why HIV conserves RNA structures near its splice sites. Those structures and its conformational dynamics can either positively or negatively impart cooperative protein-protein interactions; we seek to understand the biophysical nature of such mechanisms. We present strong evidence that the RNA interactions surrounding HIV splice sites A2 and A3 intrinsically regulate the levels of vpr and tat, respectively. Mutations within those RNA structures inhibit HIV replication by deregu- lating RNA splicing. We further contend that similar RNA-mediated cooperative mechanisms determine the ex- tent to which the cellular P-TEFb is released from 7SK snRNA and made available to stimulate HIV transcription elongation. To test the extent to which RNA-mediated cooperativity influences HIV nuclear gene expression, we have developed a technically innovative research program that integrates cutting edge biophysical and biochem- ical techniques to extract mechanistic principles about host-virus RNP complexes. We will implement this pro- gram by adopting two broadly conceptual specific aims: 1. Molecular interactions of viral RNAs and RNPs that contribute to HIV splicing and 2. Molecular interactions of 7SK snRNA and its different RNPs that contribute to HIV transcription. The success of this proposal promises to deliver unprecedented in-sights into the structural dynamics of RNA-RNA and protein-RNA interactions that control HIV gene expression and it may inform on details into molecular mechanisms that contribute to latency. This will in turn provide a foundation for identifying novel targets for cure strategies.


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 = -$1 )
2026	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	9	1/29/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$1
														Subtotal = -$1

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	8	10/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $548,574 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	9	9/8/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$548,574
2023	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	8	9/8/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $548,574

Issue Date FY: 2022 ( Subtotal = $547,010 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	8	8/1/2022	NON-COMPETING CONTINUATION	$547,010
														Subtotal = $547,010

Issue Date FY: 2021 ( Subtotal = $715,034 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	7	7/28/2021	NON-COMPETING CONTINUATION	$555,642
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	6	5/14/2021	SUPPLEMENT FOR EXPANSION	$159,392
														Subtotal = $715,034

Issue Date FY: 2020 ( Subtotal = $352,473 )
2020	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	6	8/19/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$352,473
														Subtotal = $352,473

Grand Total All Awards = $2,163,090

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Structural Biophysics of HIV Splicing and Transcriptional Control

Award Number: R01AI150830

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: 08/19/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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