PSGL-1 Restricts HIV-1 Infectivity by Blocking Virus Particle Attachment to Target Cells
Yajing Fu,
Sijia He,
Abdul Waheed,
Deemah Dabbagh,
Zheng Zhou,
Benjamin Trinité,
Zhao Wang,
Jieshi Yu,
Dan Wang,
Feng Li,
David N Levy,
Hong Shang,
Eric O Freed,
Yuntao Wu
Affiliations
Yajing Fu
Key Laboratory of AIDS Immunology of National Health Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang 110122, China
Sijia He
National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA
Abdul Waheed
Virus-Cell Interaction Section, HIV Dynamics and Replication Program, NCI-Frederick, Frederick, MD 21702 USA
Deemah Dabbagh
National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA
Zheng Zhou
National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA
Benjamin Trinité
Department of Basic Science, New York University College of Dentistry, New York, NY 10010, USA
Zhao Wang
Department of Biology and Microbiology, South Dakota State University, Brookings, SD 57007, USA
Jieshi Yu
Department of Biology and Microbiology, South Dakota State University, Brookings, SD 57007, USA
Dan Wang
Department of Biology and Microbiology, South Dakota State University, Brookings, SD 57007, USA
Feng Li
Department of Biology and Microbiology, South Dakota State University, Brookings, SD 57007, USA
David N Levy
Department of Basic Science, New York University College of Dentistry, New York, NY 10010, USA
Hong Shang
Key Laboratory of AIDS Immunology of National Health Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang 110122, China
Eric O Freed
Virus-Cell Interaction Section, HIV Dynamics and Replication Program, NCI-Frederick, Frederick, MD 21702 USA
Yuntao Wu
National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA
P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric, mucin-like, 120-kDa glycoprotein that binds to P-, E-, and L-selectins. PSGL-1 is primarily expressed on the surface of lymphoid and myeloid cells and is up-regulated during inflammation to mediate leukocyte tethering and rolling on the surface of endothelium for migration into inflamed tissues. Although it has been reported that PSGL-1 expression inhibits human immunodeficiency virus type 1 (HIV-1) replication, the mechanism of PSGL-1-mediated anti-HIV activity remains to be elucidated. Here, we report that PSGL-1 in virions blocks the infectivity of HIV-1 particles by preventing the binding of particles to target cells. This inhibitory activity is independent of the viral glycoprotein present on the virus particle; the binding of particles bearing the HIV-1 envelope glycoprotein, vesicular stomatitis virus G glycoprotein, or lacking a viral glycoprotein, is impaired by PSGL-1. Mapping studies show that the extracellular, N-terminal domain of PSGL-1 is necessary for its anti-HIV-1 activity, and the PSGL-1 cytoplasmic tail contributes to its inhibition. In addition, we demonstrate that the PSGL-1-related monomeric E-selectin-binding glycoprotein CD43 also effectively blocks HIV-1 infectivity. HIV-1 infection, or the expression of either Vpu or Nef, downregulates PSGL-1 from the cell surface; the expression of Vpu appears to be primarily responsible for enabling the virus to partially escape PSGL-1-mediated restriction. Finally, we show that PSGL-1 inhibits the infectivity of other viruses such as murine leukemia virus and influenza A virus. These findings demonstrate that PSGL-1 is a broad-spectrum antiviral host factor with a novel mechanism of action.
