title: Platelet Factor 4 Inhibits and Enhances HIV-1 Infection in a Concentration-Dependent Manner by Modulating Viral Attachment.
abstract: Platelet factor 4 (PF4) has been recently shown to inhibit infection by a broad range of human immunodeficiency virus type 1 (HIV-1) isolates in vitro. We found that the inhibitory effects of PF4 are limited to a defined concentration range where PF4 exists largely in a monomeric state. Under these conditions, PF4 bound the HIV-1 envelope protein and inhibited HIV-1 attachment to the cell surface. However, as concentrations increased to the point where PF4 exists largely in tetrameric or higher-order forms, viral infection in vitro was enhanced. Enhancement could be inhibited by mutations in PF4 that shift the oligomeric equilibrium toward the monomeric state, or by using soluble glycosaminoglycans (GAGs) to which tetrameric PF4 avidly binds. We conclude that at physiologically relevant concentrations, oligomeric PF4 enhances infection by HIV-1 by interacting with the viral envelope protein as well as cell surface GAGs, enhancing virus attachment to the cell surface. This effect was not specific to HIV-1, as enhancement was seen with some but not all other viruses tested. The biphasic effects of PF4 on HIV-1 infection suggest that native PF4 will not be a useful antiviral agent and that PF4 could contribute to the hematologic abnormalities commonly seen in HIV-infected individuals by enhancing virus infection in the bone marrow.
authors: 1 Department of Microbiology, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.
authors: Zahra F
authors: ZF
authors: Parker
authors: 2 Department of Pathology, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.
authors: Ann H
authors: AH
authors: Rux
authors: 1 Department of Microbiology, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.
authors: Amber M
authors: AM
authors: Riblett
authors: 1 Department of Microbiology, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.
authors: Fang-Hua
authors: FH
authors: Lee
authors: 3 Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.|4 Department of Hematology, Children's Hospital of Philadelphia , Philadelphia, Pennsylvania.
authors: Lubica
authors: L
authors: Rauova
authors: 2 Department of Pathology, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.
authors: Douglas B
authors: DB
authors: Cines
authors: 3 Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.|4 Department of Hematology, Children's Hospital of Philadelphia , Philadelphia, Pennsylvania.
authors: Mortimer
authors: M
authors: Poncz
authors: 2 Department of Pathology, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.|5 New York Blood Center , New York, New York.
authors: Bruce S
authors: BS
authors: Sachais
authors: 1 Department of Microbiology, University of Pennsylvania School of Medicine , Philadelphia, Pennsylvania.|6 Departments of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia , Philadelphia, Pennsylvania.
authors: Robert W
authors: RW
authors: Doms
mesh_terms: D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D010978:Platelet Factor 4 / Q000378:metabolism*; D011485:Protein Binding; D053585:Virus Attachment; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D054299:env Gene Products, Human Immunodeficiency Virus; D010978:Platelet Factor 4