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ESCRT-Related protein PTPN23 as a cofactor for HIV-1 Vpu

Award Number: R21AI172599
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: 08/09/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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ESCRT-Related protein PTPN23 as a cofactor for HIV-1 Vpu - PROJECT SUMMARY The Human Immunodeficiency Virus manipulates host cellular processes to promote synthesis of viral components, which must be appropriately localized to subcellular domains for viral budding and release. In addition to the structural Gag, Pol and Env polyproteins common to all retroviruses, HIV-1 encodes four “accessory” proteins: Vpu, Nef, Vif and Vpr, which function to promote evasion of host adaptive and innate immune responses. These viral accessory proteins co-opt host degradative and protein-trafficking processes by functioning as molecular adaptors that form ternary complexes with targeted host factors, including the intrinsic cellular immunity provided by host “restriction factors”, and components of the host trafficking machinery. Elucidation of the mechanisms by which host and viral proteins can promote or inhibit infection may lead to the identification of targets for therapeutic intervention. We have recently identified a novel HIV-1 cofactor, ESCRT-associated protein, PTPN23 (HD-PTP), which appears to function as a cofactor for Vpu activities. Transient knockdown of PTPN23 prevented Vpu-mediated degradation of BST-2 and inhibited virus release. Interestingly, PTPN23 is not only for required for BST-2 degradation, but also for surface downregulation of CD4. Furthermore, our previous (unpublished) studies support a role for clathrin and clathrin adaptor AP-2 in Vpu-mediated surface downregulation of CD4. We hypothesize that Vpu-mediated antagonism of CD4 is mediated at least in part by endocytosis and lysosomal degradation rather than exclusively by ERAD-like mechanisms. Here, we propose to determine whether PTPN23 acts as a cofactor for Vpu-mediated degradation of CD4, and elucidate the molecular mechanisms by which Vpu interacts with PTPN23. We will also validate PTPN23 as a cofactor for Vpu activities in primary T-cells to demonstrate applicability in a viral infection setting. We will further define additional components of the ESCRT pathway necessary for surface downregulation and/or degradation CD4. Elucidating the molecular interactions between Vpu and ESCRT-associated proteins will define targets for therapeutic intervention; by inhibiting Vpu's anti-immune activities we will sensitize infected cells to detection and immune clearance.


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 = -$2,047 )
2026	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	2	2/13/2026	NON-COMPETING CONTINUATION	-$2,047
														Subtotal = -$2,047

Issue Date FY: 2024 ( Subtotal = $0 )
2024	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	2	4/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $179,375 )
2023	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	2	7/13/2023	NON-COMPETING CONTINUATION	$179,375
														Subtotal = $179,375

Issue Date FY: 2022 ( Subtotal = $215,250 )
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	1	8/8/2022	NEW	$215,250
														Subtotal = $215,250

Grand Total All Awards = $392,578

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ESCRT-Related protein PTPN23 as a cofactor for HIV-1 Vpu

Award Number: R21AI172599

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: 08/09/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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