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HIV-1 Vpu and BST-2/CD317

Award Number: R37AI081668
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: 12/01/2008
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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HIV-1 Vpu and BST-2/CD317 - HIV-1 encodes proteins that modulate the host cellular environment to optimize viral replication and avoid host defenses. The accessory protein Vpu accomplishes this in part by antagonizing the activity of the host protein BST2 (also known as HM1.24, CD317, and tetherin). BST2 is an interferon-inducible integral membrane protein. This protein is the restriction factor that Vpu counteracts to stimulate the release of virus particles (virions) from infected host cells. We and others have shown that BST2 directly holds nascent virions to the plasma membrane of infected cells; that Vpu counteracts this by removing BST2 from its site of action at the plasma membrane; that BST2 is upregulated in response to HIV replication in vivo; and that BST2 serves a signaling and virus-sensing function through the induction of NF-κB transcriptional activity. The latter finding fits an emerging paradigm in which retroviral restriction factors have multifaceted roles during the innate immune response. Moreover, the field has developed evidence that HIV-1 Vpu specifically adapted to acquire activity as an antagonist of BST2 upon transmission of SIVcpz from chimpanzees to humans. Several key questions now need to be answered, and these are the basis for the specific aims of the proposal: 1) what are the molecular determinants and topologies of the protein's restricting and signaling activities? 2) in addition to the β-TrCP containing ubiquitin ligase complex, what are the cellular cofactors that support the antagonism of BST2 and how does Vpu interact with them? 3) how does BST2 activate NF-κB and detect viral gene expression? Does BST2 facilitate aspects of the adaptive immune response? And 4) does Vpu-mediated antagonism of BST2 contribute to HIV-1 transmission? Through the work proposed here, we expect to learn how the tethering and signaling functions of BST2 are structurally integrated; how Vpu modulates BST2 to antagonize restriction and signaling; the mechanisms by which BST2 signals and responds to viral gene expression and assembly; whether BST2 facilitates adaptive immunity; and whether any of the Vpu functions related to BST2 are optimized in HIV-1 variants that are transmitted between individuals. We expect to support or reject the notion that BST2-antagonism is an important aspect of HIV-1’s ability to escape immune surveillance and establish a persistent infection in the human host.


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 = $0 )
2025	2023	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	15	11/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $510,019 )
2023	2023	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	15	11/9/2022	NON-COMPETING CONTINUATION	$510,019
														Subtotal = $510,019

Issue Date FY: 2022 ( Subtotal = $510,019 )
2022	2022	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	14	11/5/2021	NON-COMPETING CONTINUATION	$510,019
														Subtotal = $510,019

Issue Date FY: 2021 ( Subtotal = $510,019 )
2021	2021	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	13	11/9/2020	NON-COMPETING CONTINUATION	$510,019
														Subtotal = $510,019

Issue Date FY: 2020 ( Subtotal = $510,019 )
2020	2020	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	12	12/3/2019	NON-COMPETING CONTINUATION	$510,019
														Subtotal = $510,019

Issue Date FY: 2019 ( Subtotal = $510,019 )
2019	2019	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	11	11/28/2018	EXTENSION WITH OR WITHOUT FUNDS	$510,019
2019	2019	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	11	5/14/2019	EXTENSION WITH OR WITHOUT FUNDS	$26,787
2019	2018	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	10	5/14/2019	NON-COMPETING CONTINUATION	-$26,787
														Subtotal = $510,019

Issue Date FY: 2018 ( Subtotal = $446,957 )
2018	2018	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	10	11/21/2017	NON-COMPETING CONTINUATION	$446,957
														Subtotal = $446,957

Issue Date FY: 2017 ( Subtotal = $446,957 )
2017	2017	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR STE 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	9	11/9/2016	NON-COMPETING CONTINUATION	$446,957
														Subtotal = $446,957

Issue Date FY: 2016 ( Subtotal = $446,957 )
2016	2016	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	8	11/18/2015	NON-COMPETING CONTINUATION	$446,957
														Subtotal = $446,957

Issue Date FY: 2015 ( Subtotal = $446,957 )
2015	2015	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	7	11/7/2014	NON-COMPETING CONTINUATION	$446,957
														Subtotal = $446,957

Issue Date FY: 2014 ( Subtotal = $446,957 )
2014	2014	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	6	11/27/2013	COMPETING CONTINUATION	$402,263
2014	2014	VETERANS MEDICAL RESEARCH FOUNDATION OF SAN DIEGO	3350 LA JOLLA VILLAGE DR 151A	SAN DIEGO	CA	92161	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	6	4/16/2014	COMPETING CONTINUATION	$44,694
														Subtotal = $446,957

Grand Total All Awards = $4,784,880

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HIV-1 Vpu and BST-2/CD317

Award Number: R37AI081668

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: 12/01/2008

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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