# Mechanisms of PSGL-1 restriction of HIV virion infectivity

> **NIH NIH R01** · GEORGE MASON UNIVERSITY · 2021 · $386,530

## Abstract

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.

## Key facts

- **NIH application ID:** 10134243
- **Project number:** 5R01AI148012-02
- **Recipient organization:** GEORGE MASON UNIVERSITY
- **Principal Investigator:** YUNTAO WU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $386,530
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134243

## Citation

> US National Institutes of Health, RePORTER application 10134243, Mechanisms of PSGL-1 restriction of HIV virion infectivity (5R01AI148012-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10134243. Licensed CC0.

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