Human Discs Large is a new negative regulator of human immunodeficiency virus-1 infectivity

Mol Biol Cell. 2009 Jan;20(1):498-508. doi: 10.1091/mbc.e08-02-0189. Epub 2008 Oct 22.

Abstract

Human immunodeficiency virus (HIV)-1 replication is positively or negatively regulated through multiple interactions with host cell proteins. We report here that human Discs Large (Dlg1), a scaffold protein recruited beneath the plasma membrane and involved in the assembly of multiprotein complexes, restricts HIV-1 infectivity. The endogenous Dlg1 and HIV-1 Gag polyprotein spontaneously interact in HIV-1-chronically infected T cells. Depleting endogenous Dlg1 in either adherent cells or T cells does not affect Gag maturation, production, or release, but it enhances the infectivity of progeny viruses five- to sixfold. Conversely, overexpression of Dlg1 reduces virus infectivity by approximately 80%. Higher virus infectivity upon Dlg1 depletion correlates with increased Env content in cells and virions, whereas the amount of virus-associated Gag or genomic RNA remains identical. Dlg1 knockdown is also associated with the redistribution and colocalization of Gag and Env toward CD63 and CD82 positive vesicle-like structures, including structures that seem to still be connected to the plasma membrane. This study identifies both a new negative regulator that targets the very late steps of the HIV-1 life cycle, and an assembly pathway that optimizes HIV-1 infectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antigens, CD / metabolism
  • Cell Line
  • Discs Large Homolog 1 Protein
  • Gene Products, gag / genetics
  • Gene Products, gag / metabolism
  • HIV-1 / genetics
  • HIV-1 / metabolism*
  • HIV-1 / pathogenicity*
  • Humans
  • Kangai-1 Protein / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Platelet Membrane Glycoproteins / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / virology
  • Tetraspanin 30
  • Virion / genetics
  • Virion / metabolism
  • env Gene Products, Human Immunodeficiency Virus / genetics
  • env Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • CD63 protein, human
  • DLG1 protein, human
  • Discs Large Homolog 1 Protein
  • Gene Products, gag
  • Kangai-1 Protein
  • Membrane Proteins
  • Platelet Membrane Glycoproteins
  • RNA, Small Interfering
  • Tetraspanin 30
  • env Gene Products, Human Immunodeficiency Virus