The frequently reported amino acid covariation of the highly polymorphic human immunodeficiency virus type 1 (HIV-1) exterior envelope glycoprotein V3 region has been assumed to reflect fitness epistasis between residues. However, nonrandom association of amino acids, or linkage disequilibrium, has many possible causes, including population subdivision. If the amino acids at a set of sequence sites differ in frequencies between subpopulations, then analysis of the whole population may reveal linkage disequilibrium even if it does not exist in any subpopulation. HIV-1 has a complex population structure, and the effects of this structure on linkage disequilibrium were investigated by estimating within- and among-subpopulation components of variance in linkage disequilibrium. The amino acid covariation previously reported is explained by differences in amino acid frequencies among virus subpopulations in different patients and by nonsystematic disequilibrium among patients. Disequilibrium within patients appears to be entirely due to differences in amino acid frequencies among sampling time points and among chemokine coreceptor usage phenotypes of virus particles, but not source tissues. Positive selection explains differences in allele frequencies among time points and phenotypes, indicating that these differences are adaptive rather than due to genetic drift. However, the absence of a correlation between linkage disequilibrium and phenotype suggests that fitness epistasis is an unlikely cause of disequilibrium. Indeed, when population structure is removed by analyzing sequences from a single time point and phenotype, no disequilibrium is detectable within patients. These results caution against interpreting amino acid covariation and coevolution as evidence for fitness epistasis
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