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Regulation and Targeting of HIV-1 Integrase-RNA Interactions

Award Number: R01AI150497
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: 01/01/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Regulation and Targeting of HIV-1 Integrase-RNA Interactions - Abstract The emergence of drug resistant human immunodeficiency virus type-1 (HIV-1) variants and the lack of an effective vaccine require the development of novel anti-retroviral drugs. The catalytic activity of HIV-1 integrase (IN) has been successfully targeted by several highly effective and well tolerated IN strand transfer inhibitors (INSTIs). However, despite high barriers with the second-generation INSTIs, mutations conferring resistance to multiple INSTIs have been reported in clinical settings. Thus, targeting IN through an alternative mechanism can complement the existing therapeutic strategies and substantially increase the barrier to emergence of drug resistant HIV-1 variants upon INSTI treatment. IN has long been known to have an enigmatic non-catalytic function in the HIV-1 life cycle. Certain mutations in IN, collectively referred to as class II mutations, are reportedly pleiotropic and result in defects in viral particle assembly, maturation and reverse transcription. In a paradigm-shifting study, we have discovered that HIV-1 IN binds to the viral RNA genome (gRNA) in virions and that this interaction is critically important for accurate virion morphogenesis. Inhibition of IN-gRNA interactions through allosteric integrase inhibitors (ALLINIs) or class II IN substitutions results in the formation of aberrant “eccentric” particles with the gRNA is mislocalized between the empty capsid (CA) lattice and the viral envelope. Furthermore, we have shown that IN tetramerization is critical for RNA-binding and that a number of class II IN substitutions located throughout IN inhibit RNA binding through modulation of IN tetramerization. Finally, work from our lab demonstrated that premature degradation of the gRNA and its physical separation from the reverse transcriptase enzyme in virions underlies the reverse transcription defects of eccentric particles in target cells. Importantly, this untimely gRNA degradation is not due to inhibition of IN-gRNA interactions per se, but rather due to loss of protection with the CA lattice, as a similar outcome was observed upon CA destabilization. Together, these studies cemented the role of IN-gRNA interactions in virion maturation and demonstrated the critical importance of the CA lattice in protection of viral nucleic acids in target cells. Based on these novel findings and extensive preliminary data, we propose to elucidate the nature and rules of HIV-1 IN-gRNA interactions, how IN binding to the gRNA mediates proper assembly of the HIV-1 capsid lattice and how infected cells sense and respond to aberrant particles generated upon inhibition of IN-gRNA interactions and destabilization of the CA lattice. These studies will fill a critical gap in our understanding of the critical noncatalytic function of HIV-1 IN in particle maturation and the consequences of inhibiting these interactions. Together, this project will not only enhance our basic knowledge of HIV-1 replication but also aid in the development of novel antivirals that can complement INSTI-based therapies in clinical settings.


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 = $452,504 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	9	1/15/2025	NON-COMPETING CONTINUATION	$452,504
														Subtotal = $452,504

Issue Date FY: 2024 ( Subtotal = $466,500 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	8	10/31/2023	NON-COMPETING CONTINUATION	$419,851
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	001	8	5/16/2024	NON-COMPETING CONTINUATION	$46,649
														Subtotal = $466,500

Issue Date FY: 2023 ( Subtotal = $470,000 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	7	11/10/2022	NON-COMPETING CONTINUATION	$470,000
														Subtotal = $470,000

Issue Date FY: 2022 ( Subtotal = $472,500 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	002	6	1/11/2022	COMPETING CONTINUATION	$99,225
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	004	6	8/25/2022	COMPETING CONTINUATION	$3,270
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	6	11/4/2021	COMPETING CONTINUATION	$373,275
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	001	6	12/21/2021	COMPETING CONTINUATION	$0
2022	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	003	5	8/25/2022	NON-COMPETING CONTINUATION	-$3,270
														Subtotal = $472,500

Issue Date FY: 2021 ( Subtotal = $301,188 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	5	11/18/2020	NON-COMPETING CONTINUATION	$301,188
														Subtotal = $301,188

Issue Date FY: 2020 ( Subtotal = $301,188 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	4	11/25/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$301,188
														Subtotal = $301,188

Grand Total All Awards = $2,463,880

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Regulation and Targeting of HIV-1 Integrase-RNA Interactions

Award Number: R01AI150497

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: 01/01/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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