Inhibition of HIV-1 progeny virion release by cell-surface CD4 is relieved by expression of the viral Nef protein

Curr Biol. 1999 Jun 17;9(12):613-21. doi: 10.1016/s0960-9822(99)80283-8.

Abstract

Background: The human immunodeficiency virus type 1 (HIV-1) Nef protein is required for efficient virus replication in vivo and displays a number of distinct and apparently unrelated biological activities in vitro. Of these, one of the most readily demonstrated is the efficient internalization and degradation of cell-surface CD4, the receptor for the HIV-1 envelope protein. The biological purpose of this internalization has, however, remained unclear.

Results: Using human 293T cells expressing high levels of cell-surface CD4 or CD8, we demonstrate that CD4, but not CD8, can dramatically reduce the release of infectious virions bearing the HIV-1 envelope protein and induce a concomitant increase in the accumulation of cell-associated HIV-1 structural proteins. In contrast, CD4 had no effect on the release of HIV-1 bearing a heterologous envelope protein unable to bind CD4. Nef expression totally reversed CD4-mediated inhibition but only if the CD4 used remained susceptible to Nef-induced internalization.

Conclusions: These results support the hypothesis that cell-surface CD4 can interact with the envelope protein present on budding HIV-1 virions to inhibit their release. The internalization and degradation of cell-surface CD4 induced by the viral Nef protein can fully reverse this inhibition and is, therefore, likely to facilitate the spread of virus in vivo.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • CD4 Antigens / genetics
  • CD4 Antigens / physiology*
  • CD8 Antigens / physiology
  • Cell Line
  • Down-Regulation
  • Gene Expression
  • Gene Products, env / physiology
  • Gene Products, nef / chemistry
  • Gene Products, nef / genetics
  • Gene Products, nef / physiology*
  • Genes, nef
  • HIV Infections / virology
  • HIV-1 / genetics
  • HIV-1 / physiology*
  • Humans
  • Transfection
  • Virus Replication
  • nef Gene Products, Human Immunodeficiency Virus
  • src Homology Domains

Substances

  • CD4 Antigens
  • CD8 Antigens
  • Gene Products, env
  • Gene Products, nef
  • nef Gene Products, Human Immunodeficiency Virus