Mechanisms of CD4 downregulation by the Nef and Vpu proteins of primate immunodeficiency viruses

Curr Mol Med. 2007 Mar;7(2):171-84. doi: 10.2174/156652407780059177.


Human immunodeficiency virus type 1 (HIV-1), human immunodeficiency virus type 2 (HIV-2), and simian immunodeficiency virus (SIV) are the etiological agents of acquired immunodeficiency syndrome (AIDS) in humans and a related disease in non-human primates. These viruses infect T cells and macrophages that express the surface glycoprotein, CD4, because this glycoprotein acts as a co-receptor for incoming virus particles. Once infection has occurred, however, the presence of CD4 poses problems for the virus life cycle, including the possibility of superinfection, premature binding of CD4 to nascent virus particles, and inhibition of virus release. Accordingly, primate immunodeficiency viruses have evolved at least two distinct mechanisms, mediated by the Nef and Vpu viral proteins, to "downregulate" CD4 in the host cells. Nef and Vpu are mainly expressed early and late, respectively, in the viral life cycle, ensuring continuous removal of CD4. Nef links mature CD4 to components of clathrin-dependent trafficking pathways at the plasma membrane, and perhaps in intracellular compartments, leading to internalization and delivery of CD4 to lysosomes for degradation. Vpu, on the other hand, interacts with newly-synthesized CD4 in the endoplasmic reticulum, linking CD4 to the SCF ubiquitin ligase and facilitating the entry of CD4 into the endoplasmic-reticulum-associated degradation pathway. These two mechanisms lead to a dramatic reduction of CD4 expression in infected cells and are essential for efficient virus replication and disease progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Vesicular Transport / chemistry
  • Adaptor Proteins, Vesicular Transport / physiology
  • Animals
  • CD4 Antigens / metabolism*
  • Down-Regulation
  • Gene Products, nef / chemistry
  • Gene Products, nef / physiology*
  • Human Immunodeficiency Virus Proteins
  • Humans
  • Lentiviruses, Primate / pathogenicity*
  • Lentiviruses, Primate / physiology
  • Models, Biological
  • Models, Molecular
  • Multiprotein Complexes
  • Primates
  • Protein Binding
  • Viral Regulatory and Accessory Proteins / chemistry
  • Viral Regulatory and Accessory Proteins / physiology*
  • beta-Transducin Repeat-Containing Proteins / chemistry
  • beta-Transducin Repeat-Containing Proteins / physiology
  • nef Gene Products, Human Immunodeficiency Virus


  • Adaptor Proteins, Vesicular Transport
  • CD4 Antigens
  • Gene Products, nef
  • Human Immunodeficiency Virus Proteins
  • Multiprotein Complexes
  • Viral Regulatory and Accessory Proteins
  • beta-Transducin Repeat-Containing Proteins
  • nef Gene Products, Human Immunodeficiency Virus
  • vpu protein, Human immunodeficiency virus 1