title: A recombinant vesicular stomatitis virus encoding CCR5-tropic HIV-1 receptors targets HIV-1-infected cells and controls HIV-1 infection.
abstract: Anti-retroviral therapy is useful to treat human immunodeficiency virus type 1 (HIV-1)-infected individuals, but has some major problems, such as the generation of multidrug-resistant viruses. To develop a novel supplemental or alternative therapeutic for CCR5-tropic (R5) HIV-1 infection, we generated a recombinant vesicular stomatitis virus (rVSV) in which the gene encoding its envelope glycoprotein (G) was replaced with the genes encoding R5 HIV-1 receptors (human CD4 and CCR5), designated VSVΔG-CC5. Our present data demonstrate that this rVSV specifically infects cells that are transiently expressing R5 HIV-1 envelope glycoproteins, but does not infect those expressing CXCR4-tropic HIV-1 envelope glycoproteins. Notably, after a CD4+CCR5+T cell line or primary cells initially infected with R5 HIV-1 were inoculated with G-complemented VSVΔG-CC5, the rVSV significantly reduced the number of HIV-1-infected cells, probably through direct targeting of the rVSV and VSV-mediated cytolysis and/or through syncytium formation- or cell-cell fusion-dependent killing, and markedly inhibited HIV-1 production. Furthermore, G-complemented VSVΔG-CC5 also efficiently inhibited HIV-1 infection in R5 HIV-1-infected humanized immunodeficient mice. Taken together, our findings indicate that a cytolytic rVSV that targets and eliminates R5 HIV-1-infected cells potentially has therapeutic value for controlling R5 HIV-1 infection.
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo, Japan. Electronic address: kokuma@niid.go.jp.
authors.forename: Kazu
authors.initials: K
authors.lastname: Okuma
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo, Japan; Technology and Product Development Division, Diagnostic Reagent Development, Sysmex Corporation, Kobe, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Fukagawa
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo, Japan; Technology and Product Development Division, Diagnostic Reagent Development, Sysmex Corporation, Kobe, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kohma
authors.affiliation: Technology and Product Development Division, Diagnostic Reagent Development, Sysmex Corporation, Kobe, Japan.
authors.forename: Youichi
authors.initials: Y
authors.lastname: Takahama
authors.affiliation: Technology and Product Development Division, Diagnostic Reagent Development, Sysmex Corporation, Kobe, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hamaguchi
authors.affiliation: Central Institute of Experimental Animals, Kanagawa, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Pathology, Yale University School of Medicine, CT, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Buonocore
authors.affiliation: Department of Pathology, Yale University School of Medicine, CT, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Rose
authors.affiliation: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Hamaguchi
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D015704:CD4 Antigens / Q000235:genetics* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D006224:Cricetinae; D057809:HEK293 Cells; D015658:HIV Infections / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D019713:Receptors, CCR5 / Q000235:genetics* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D018116:Vesiculovirus / Q000235:genetics*; D014759:Viral Envelope Proteins / Q000235:genetics*; D019562:Viral Load; D014779:Virus Replication / Q000235:genetics*
chemical_list: D000998:Antiviral Agents; C584933:CCR5 protein, human; D015704:CD4 Antigens; C527276:CXCR4 protein, human; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D014759:Viral Envelope Proteins
keywords: Envelope; Human immunodeficiency virus type 1; Infection; Receptor; Therapy; Vesicular stomatitis virus