EVOLUTION OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 SUBTYPE-SPECIFICV3 DOMAIN IS CONFINED TO A SEQUENCE SPACE WITH A FIXED DISTANCE TO THE SUBTYPE CONSENSUS

Human immunodeficiency virus type 1 (HIV-1) strains can be separated i nto genetic subtypes based on phylogenetic analysis of the envelope ge ne, Once it had been shown that population-wide intrasubtype genetic v ariation of HIV-1 strains increases in the course of the AIDS epidemic , it remained uncertain whether HIV-1 subtypes are phenotypic entities spreading as distinct virus populations, To examine this, we applied Eigen's concepts of sequence geometry and fitness topography to the an alysis of intrasubtype evolution of the gp120 V3 domain of HIV-1 subty pes A, B, C, and D in the course of the global AIDS epidemic, We obser ved that despite the high evolution rate of HIV-1, the nonsynonymous d istances to the subtype consensus of sequences obtained early in the e pidemic are similar to those obtained more than 10 gears later, in con trast to the synonymous distances, which increased steadily over time, For HIV-1 subtype B, we observed that the evolution rate of the indiv idual sequences is independent of their distance from the subtype B co nsensus, but for the individual sequences most distant from the consen sus evolution away from the consensus is constrained, As a result, ind ividual HIV-1 genomes fluctuate within a sequence space with fixed dis tance to the subtype consensus, Our findings suggest that the evolutio n of the V3 domain of HIV-1 subtypes A, B, C, and D is confined to an area in sequence space within a fixed distance to the consensus of a r espective subtype. This in turn indicates that each HIV-1 subtype is a distinct viral quasispecies that is well adapted to the present envir onment, able to maintain its identity in the V3 region over time, and unlikely to merge during progression of the AIDS epidemic.