Tetherin-driven adaptation of Vpu and Nef function and the evolution of pandemic and nonpandemic HIV-1 strains

Cell Host Microbe. 2009 Nov 19;6(5):409-21. doi: 10.1016/j.chom.2009.10.004.


Vpu proteins of pandemic HIV-1 M strains degrade the viral receptor CD4 and antagonize human tetherin to promote viral release and replication. We show that Vpus from SIVgsn, SIVmus, and SIVmon infecting Cercopithecus primate species also degrade CD4 and antagonize tetherin. In contrast, SIVcpz, the immediate precursor of HIV-1, whose Vpu shares a common ancestry with SIVgsn/mus/mon Vpu, uses Nef rather than Vpu to counteract chimpanzee tetherin. Human tetherin, however, is resistant to Nef and thus poses a significant barrier to zoonotic transmission of SIVcpz to humans. Remarkably, Vpus from nonpandemic HIV-1 O strains are poor tetherin antagonists, whereas those from the rare group N viruses do not degrade CD4. Thus, only HIV-1 M evolved a fully functional Vpu following the three independent cross-species transmissions that resulted in HIV-1 groups M, N, and O. This may explain why group M viruses are almost entirely responsible for the global HIV/AIDS pandemic.

Publication types

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

MeSH terms

  • Acquired Immunodeficiency Syndrome / epidemiology
  • Acquired Immunodeficiency Syndrome / virology
  • Amino Acid Sequence
  • Animals
  • Antigens, CD / physiology*
  • CD4 Antigens / genetics*
  • Cell Line
  • Cercopithecus
  • Evolution, Molecular
  • GPI-Linked Proteins
  • Gene Expression Regulation
  • HIV-1 / pathogenicity
  • HIV-1 / physiology
  • Human Immunodeficiency Virus Proteins / genetics
  • Humans
  • Membrane Glycoproteins / physiology*
  • Molecular Sequence Data
  • Sequence Alignment
  • Simian Immunodeficiency Virus / pathogenicity
  • Simian Immunodeficiency Virus / physiology
  • Viral Regulatory and Accessory Proteins / genetics
  • Zoonoses
  • nef Gene Products, Human Immunodeficiency Virus / genetics


  • Antigens, CD
  • BST2 protein, human
  • CD4 Antigens
  • GPI-Linked Proteins
  • Human Immunodeficiency Virus Proteins
  • Membrane Glycoproteins
  • NEF protein, SIV
  • Viral Regulatory and Accessory Proteins
  • nef Gene Products, Human Immunodeficiency Virus
  • vpu protein, Human immunodeficiency virus 1

Associated data

  • GENBANK/GQ925923
  • GENBANK/GQ925924
  • GENBANK/GQ925925
  • GENBANK/GQ925926
  • GENBANK/GQ925927
  • GENBANK/GQ925928
  • GENBANK/GQ925929
  • GENBANK/GQ925930
  • GENBANK/GQ925931
  • GENBANK/GQ925932
  • GENBANK/GQ925933
  • GENBANK/GQ925934
  • GENBANK/GQ925935
  • GENBANK/GQ925936
  • GENBANK/GQ925937
  • GENBANK/GQ925938
  • GENBANK/GQ925939
  • GENBANK/GQ925940
  • GENBANK/GQ925941
  • GENBANK/GQ925942
  • GENBANK/GQ925943
  • GENBANK/GQ925944
  • GENBANK/GQ925945
  • GENBANK/GQ925946
  • GENBANK/GQ925947
  • GENBANK/GQ925948
  • GENBANK/GQ925949
  • GENBANK/GQ925950
  • GENBANK/GQ925951