Rapid evolution by positive Darwinian selection in T-cell antigen CD4 in primates

Zhengdong D. Zhang, George Weinstock, Mark Gerstein

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


CD4, an integral membrane glycoprotein, plays a critical role in the immune response and in the life cycle of simian and human immunodeficiency virus (SIV and HIV). Pairwise comparisons of orthologous human and mouse genes show that CD4 is evolving much faster than the majority of mammalian genes. The acceleration is too great to be attributed to a simple relaxation of the action of purifying selection alone. Here we show that the selective pressure acting on CD4 is highly variable between regions in the protein and identify codon sites under strong positive selection. We reconstruct the coding sequences for ancestral primate CD4s and model tertiary structures of all ancestral and extant sequences. Structural mapping of positively selected sites shows they distribute on the surface of the D1 domain of CD4, where the exogenous SIV gp120 protein binds. Moreover, structural models of the ancestral sequences show substantially larger variation in the interfacial electrostatic charge on CD4 and in the surface complementary between CD4 and gp120 in CD4 lineages from primates with natural SIV infections than those without. Thus, positive selection on CD4 among primates may reflect forces driven by SIV infection and could provide a link between changes in sequence and structure of CD4 during evolution and the interaction with the immunodeficiency virus.

Original languageEnglish (US)
Pages (from-to)446-456
Number of pages11
JournalJournal of Molecular Evolution
Issue number5
StatePublished - May 2008
Externally publishedYes


  • CD4
  • Human immunodeficiency virus
  • Lentivirus
  • Molecular adaptation
  • Positive selection
  • Protein evolution
  • Simian immunodeficiency virus
  • gp120

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics


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