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Mechanisms of PSGL-1 restriction of HIV virion infectivity

Award Number: R01AI148012
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: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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Mechanisms of PSGL-1 restriction of HIV virion infectivity - Project Summary: PSGL-1 is a recently discovered Vpu-antagonized HIV restriction factor. The protein is a mucin-like glycoprotein primarily expressed on the surface of lymphoid and myeloid cells. PSGL-1 binds to P-, L-, and E-selectin to mediate leukocyte tethering and rolling on the surface of endothelium for T cell transmigration into inflamed tissues. Structurally, PSGL-1 has a relatively rigid and elongated extracellular domain (EC) that can extend approximately 60 nm from the cell surface. EC is mainly composed of 14 to 16 repeats of decamers made up of 10 amino acids. These decameric repeats (DR) feature a varied proportion of O-glycosylated threonines and prolines, which are critical for enhancing the backbone structure of PSGL-1, allowing the selectin-binding sites to be well-extended from the cell surface to support leukocyte rolling. For restricting HIV, PSGL-1 is incorporated onto virion particles, and the presence of PSGL-1 on the surface of HIV can sterically hinder HIV binding to target cells. As an antagonism, HIV utilizes multiple viral proteins such as Vpu, Nef, and Gag to downregulate PSGL-1 to reduce its virion incorporation for maintaining virus infectivity. Our central hypothesis is that PSGL-1's DR serves as the fundamental molecular unit driving PSGL-1's antiviral function; in addition, HIV-mediated PSGL-1 downregulation affects HIV+ T cell transmigration, directly impacting reservoir distribution and persistence in the body. The overall goal of the project is to understand the antiviral mechanisms of PSGL-1 and its glycosylation regulation, as well as the impacts of HIV-mediated PSGL-1 downregulation on reservoir persistence in patients. The proposed studies have 3 specific aims. Aim 1 is to understand the structure-function relationship of PSGL-1 DR as a basic antiviral unit. We have developed mathematic structure-function models to analyze DR conformations. We plan to construct and test a substantial collection of DR mutants (80-100) based on our modeling. We anticipate identifying vital amino acids and their patten of distribution along the DR backbone that are critical for PSGL-1's anti-HIV activity. We will also apply the knowledge to develop novel PSGL-1 variants with enhanced antiviral activity for inactivating viral reservoirs. Aim 2 is to understand the role of T cell glycosylation systems in regulating PSGL-1's antiviral activity. We will investigate the relationship between cellular glycosylation systems and PSGL-1's antiviral activity. We will also profile PSGL-1 glycosylation on plasma virions released from reservoirs for the first time. Aim 3 is to understand the impact of HIV-mediated PSGL-1 downregulation on reservoir persistence. We hypothesize that HIV-mediated PSGL-1 downregulation directly impacts tissue distribution of HIV+ reservoir T cells in the body. We will sort reservoir T cells from the peripheral blood and rectal tissues of HIV patients, based both on the levels and the functions of PSGL-1. We will study the impacts of PSGL-1 on reservoir tissue distribution. The significance of these proposed studies lies in their potential to elucidate novel antiviral mechanisms, and sheds new lights on tissue persistence of HIV reservoirs.


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 = $3,069,507 )
2026	2026	GEORGE MASON UNIVERSITY	4400 UNIVERSITY DR	FAIRFAX	VA	22030	FAIRFAX CITY	USA	Allergy and Infectious Diseases Research	001	6	8/18/2026	COMPETING CONTINUATION	$3,069,512
2026	2024	GEORGE MASON UNIVERSITY	4400 UNIVERSITY DR	FAIRFAX	VA	22030	FAIRFAX CITY	USA	Allergy and Infectious Diseases Research	000	5	7/30/2026	NON-COMPETING CONTINUATION	-$5
														Subtotal = $3,069,507

Issue Date FY: 2024 ( Subtotal = $385,591 )
2024	2024	GEORGE MASON UNIVERSITY	4400 UNIVERSITY DR	FAIRFAX	VA	22030	FAIRFAX CITY	USA	Allergy and Infectious Diseases Research	000	5	4/1/2024	NON-COMPETING CONTINUATION	$385,591
														Subtotal = $385,591

Issue Date FY: 2023 ( Subtotal = $385,928 )
2023	2023	GEORGE MASON UNIVERSITY	4400 UNIVERSITY DR	FAIRFAX	VA	22030	FAIRFAX CITY	USA	Allergy and Infectious Diseases Research	000	4	3/20/2023	NON-COMPETING CONTINUATION	$385,928
														Subtotal = $385,928

Issue Date FY: 2022 ( Subtotal = $386,241 )
2022	2022	GEORGE MASON UNIVERSITY	4400 UNIVERSITY DR	FAIRFAX	VA	22030	FAIRFAX CITY	USA	Allergy and Infectious Diseases Research	000	3	3/17/2022	NON-COMPETING CONTINUATION	$386,241
														Subtotal = $386,241

Issue Date FY: 2021 ( Subtotal = $386,530 )
2021	2021	GEORGE MASON UNIVERSITY	4400 UNIVERSITY DR	FAIRFAX	VA	22030	FAIRFAX CITY	USA	Allergy and Infectious Diseases Research	000	2	3/5/2021	NON-COMPETING CONTINUATION	$386,530
														Subtotal = $386,530

Issue Date FY: 2020 ( Subtotal = $386,797 )
2020	2020	GEORGE MASON UNIVERSITY	4400 UNIVERSITY DR	FAIRFAX	VA	22030	FAIRFAX CITY	USA	Allergy and Infectious Diseases Research	000	1	3/27/2020	NEW	$386,797
														Subtotal = $386,797

Grand Total All Awards = $5,000,594

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Mechanisms of PSGL-1 restriction of HIV virion infectivity

Award Number: R01AI148012

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: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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