Cell-surface expression of CD4 reduces HIV-1 infectivity by blocking Env incorporation in a Nef- and Vpu-inhibitable manner

Curr Biol. 1999 Jun 17;9(12):622-31. doi: 10.1016/s0960-9822(99)80284-x.


Background: Human immunodeficiency virus-1 (HIV-1) infection decreases the cell-surface expression of its cellular receptor, CD4, through the combined actions of Nef, Env and Vpu. Such functional convergence strongly suggests that CD4 downregulation is critical for optimal viral replication, yet the significance of this phenomenon has so far remained a puzzle.

Results: We show that high levels of CD4 on the surface of HIV-infected cells induce a dramatic reduction in the infectivity of released virions by the sequestering of the viral envelope by CD4. CD4 is able to accumulate in viral particles while at the same time blocking incorporation of Env into the virion. Nef and Vpu, through their ability to downregulate CD4, counteract this effect.

Conclusions: The CD4-mediated 'envelope interference' described here probably explains the plurality of mechanisms developed by HIV to downregulate the cell-surface expression of its receptor.

Publication types

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

MeSH terms

  • CD4 Antigens / genetics
  • CD4 Antigens / physiology*
  • Cell Line
  • Cell Membrane / physiology
  • Cell Membrane / virology
  • Down-Regulation
  • Gene Products, env / physiology*
  • Gene Products, nef / antagonists & inhibitors
  • HIV Infections / virology
  • HIV-1 / pathogenicity*
  • HIV-1 / physiology*
  • Human Immunodeficiency Virus Proteins
  • Humans
  • Models, Biological
  • Viral Regulatory and Accessory Proteins / antagonists & inhibitors
  • Virus Replication
  • nef Gene Products, Human Immunodeficiency Virus


  • CD4 Antigens
  • Gene Products, env
  • Gene Products, nef
  • Human Immunodeficiency Virus Proteins
  • Viral Regulatory and Accessory Proteins
  • nef Gene Products, Human Immunodeficiency Virus
  • vpu protein, Human immunodeficiency virus 1