A recombinant vesicular stomatitis virus encoding CCR5-tropic HIV-1 receptors targets HIV-1-infected cells and controls HIV-1 infection

Microbes Infect. 2017 Apr-May;19(4-5):277-287. doi: 10.1016/j.micinf.2016.12.004. Epub 2016 Dec 24.

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.

Keywords: Envelope; Human immunodeficiency virus type 1; Infection; Receptor; Therapy; Vesicular stomatitis virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • CD4 Antigens / genetics*
  • CD4 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • Cell Line
  • Cricetinae
  • HEK293 Cells
  • HIV Infections / prevention & control*
  • HIV Infections / virology
  • HIV-1 / genetics
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Oncolytic Virotherapy / methods*
  • Receptors, CCR5 / genetics*
  • Receptors, CCR5 / metabolism
  • Receptors, CXCR4 / metabolism
  • Vesiculovirus / genetics*
  • Viral Envelope Proteins / genetics*
  • Viral Load
  • Virus Replication / genetics*

Substances

  • Antiviral Agents
  • CCR5 protein, human
  • CD4 Antigens
  • CXCR4 protein, human
  • Receptors, CCR5
  • Receptors, CXCR4
  • Viral Envelope Proteins