Transitions to and from the CD4-bound conformation are modulated by a single-residue change in the human immunodeficiency virus type 1 gp120 inner domain

J Virol. 2009 Sep;83(17):8364-78. doi: 10.1128/JVI.00594-09. Epub 2009 Jun 17.


Binding to the primary receptor CD4 induces conformational changes in the human immunodeficiency virus type 1 (HIV-1) gp120 envelope glycoprotein that allow binding to the coreceptor (CCR5 or CXCR4) and ultimately trigger viral membrane-cell membrane fusion mediated by the gp41 transmembrane envelope glycoprotein. Here we report the derivation of an HIV-1 gp120 variant, H66N, that confers envelope glycoprotein resistance to temperature extremes. The H66N change decreases the spontaneous sampling of the CD4-bound conformation by the HIV-1 envelope glycoproteins, thus diminishing CD4-independent infection. The H66N change also stabilizes the HIV-1 envelope glycoprotein complex once the CD4-bound state is achieved, decreasing the probability of CD4-induced inactivation and revealing the enhancing effects of soluble CD4 binding on HIV-1 infection. In the CD4-bound conformation, the highly conserved histidine 66 is located between the receptor-binding and gp41-interactive surfaces of gp120. Thus, a single amino acid change in this strategically positioned gp120 inner domain residue influences the propensity of the HIV-1 envelope glycoproteins to negotiate conformational transitions to and from the CD4-bound state.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • CD4 Antigens / metabolism*
  • Cell Line
  • HIV Envelope Protein gp120 / genetics*
  • HIV Envelope Protein gp120 / metabolism*
  • HIV-1 / physiology*
  • Humans
  • Mutagenesis, Site-Directed
  • Mutation, Missense
  • Protein Binding
  • Protein Conformation
  • Virus Attachment*


  • CD4 Antigens
  • HIV Envelope Protein gp120
  • gp120 protein, Human immunodeficiency virus 1