Mechanisms of PSGL-1 restriction of HIV virion infectivity

Information

  • Research Project
  • 10134243
  • ApplicationId
    10134243
  • Core Project Number
    R01AI148012
  • Full Project Number
    5R01AI148012-02
  • Serial Number
    148012
  • FOA Number
    PA-19-056
  • Sub Project Id
  • Project Start Date
    4/1/2020 - 4 years ago
  • Project End Date
    3/31/2025 - 9 months from now
  • Program Officer Name
    REFSLAND, ERIC WILLIAM
  • Budget Start Date
    4/1/2021 - 3 years ago
  • Budget End Date
    3/31/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    02
  • Suffix
  • Award Notice Date
    3/5/2021 - 3 years ago
Organizations

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-?-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.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R01
  • Administering IC
    AI
  • Application Type
    5
  • Direct Cost Amount
    250000
  • Indirect Cost Amount
    136530
  • Total Cost
    386530
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
    SCHOOLS OF ARTS AND SCIENCES
  • Funding ICs
    NIAID:386530\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    GEORGE MASON UNIVERSITY
  • Organization Department
    PUBLIC HEALTH & PREV MEDICINE
  • Organization DUNS
    077817450
  • Organization City
    FAIRFAX
  • Organization State
    VA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    220304422
  • Organization District
    UNITED STATES