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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: 03/31/2025

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Mechanisms of PSGL-1 restriction of HIV virion infectivity - Project Summary/Abstract Mechanisms of PSGL-1 restriction of HIV virion infectivity Restriction factors are an important component of host innate immunity. Studying the anti-HIV mechanisms of restriction factors is central to understanding virus-host interaction. These mechanisms may also offer new therapeutic strategies to inactivate viral reservoirs to achieve lasting HIV remission. Recently, we have identified a new HIV restriction factor, PSGL-1 (P-selectin glycoprotein ligand-1), that can inactivate the infectivity of HIV virions released from HIV producing cells. PSGL-1 is a dimeric mucin-like 120-KD glycoprotein that is primarily expressed on the surface of lymphoid and myeloid cells. PSGL-1 binds to P-, L-, and E-selectin, and mediates leukocyte tethering and rolling on endothelium for leukocyte migration into inflamed tissues. PSGL-1 is also an INF-γ-regulated factor involved in Th1-mediated anti-viral activity. Our preliminary mechanistic studies further revealed that PSGL-1 is incorporated into viral particles, which blocks HIV Env incorporation and disables the ability of virions to attach to target CD4 T cells for infection. In addition, we found that PSGL-1 is antagonized by Vpu and Nef through surface down-regulation. Based on these preliminary studies, we hypothesize that: (1) PSGL-1-mediated restriction of HIV infectivity involves its specific domains; (2) PSGL-1 restricts HIV infectivity likely through competitive exclusion of Env incorporation during viral assembly and steric hindrance of Env binding to cell receptors (3) Nef-mediated PSGL-1 down-regulation is likely achieved through linking PSGL-1 to components of clathrin-dependent trafficking pathways. In this application, we will pursue the following aims: Specific Aim 1 is to characterize PSGL-1 for inactivating HIV infectivity. We propose to identify PSGL-1 domains key to restricting HIV-1. We will determine the structure-function relationship of PSGL-1, defining the roles of PSGL-1 dimerization, N- terminal glycosylation and tyrosine sulfation, N-terminal decameric repeats, and the polybasic region in restricting HIV. Specific Aim 2 is to perform mechanistic studies of PSGL-1 inactivation of HIV viral infectivity. We hypothesized that PSGL-1 restricts HIV infectivity likely through two possible mechanisms: (1) competitive exclusion of Env incorporation during viral assembly; (2) steric hindrance of residual Env binding to cell receptors. We will test these two hypotheses to determine the mechanisms of action. Specific Aim 3 is to study the mechanism of Nef-mediated surface down-regulation of PSGL-1. We will identify functional domains of Nef and PSGL-1 for their involvement in PSGL-1 down-regulation. Nef-mediated PSGL-1 downregulation may facilitate viral spread in immune cells.


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: 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 = $1,931,087

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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: 03/31/2025

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