Evolution of the structural proteins of human immunodeficiency virus: selective constraints on nucleotide substitution.

We have estimated the frequency of synonymous (KS) and amino acid replacement nucleotide substitutions (KA) among gag and env genes of published HIV sequences. The ratio of KS to KA can be used as an indicator of the intensity of the selective constraints on the amino acid sequence of a protein. By this approach we have shown that for both gp120 and gp41, the rate of change in amino acid sequence relative to the overall rate of change in nucleotide sequence is higher than for any other protein yet analyzed. The gag proteins p15 and p17 evolve slightly less rapidly, but p24 is relatively strongly conserved. We have compared the env gene of HIV with those of two other retroviruses for which appropriate data are available. In neither murine leukemia virus nor feline leukemia virus do the envelope glycoproteins evolve particularly rapidly. These results suggest that HIV is unusual among retroviruses in that both gp120 and gp41 are evolving under extremely weak selective constraints relative to the rest of the viral genome; accordingly, much of the observed variation may be selectively neutral.