INTRAHOST HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 EVOLUTION IS RELATED TOLENGTH OF THE IMMUNOCOMPETENT PERIOD

The antigenic diversity threshold theory predicts that antigenic sites of human immunodeficiency virus type 1, such as the V3 region of the external glycoprotein gp120, evolve more rapidly during the symptom-fr ee period in individuals progressing to AIDS than in those who remain asymptomatic for a long time. To test this hypothesis, genomic RNA seq uences were obtained from the sera of 44 individuals at seroconversion and 5 years later. The mean number of nonsynonymous nucleotide substi tutions in the V3 region of the viruses circulating in 31 nonprogresso rs (1.1 x 10(-2) +/- 0.1 x 10(-2) per site per year) was higher than t he corresponding value for 13 progressors (0.66 x 10(-2) +/- 0.1 x 10( -2) per site per year) (P < 0.01), while no difference between the mea n numbers of synonymous substitutions in the two groups was seen (0.37 x 10(-2) +/- 0.1 x 10(-2) and 0.51 x 10(-2) +/- 0.2 x 10(-2) per site per year for nonprogressors and progressors, respectively; P > 0.1). The mean ratios of synonymous nucleotide distance to nonsynonymous dis tance were 0.35 for nonprogressors and 0.62 for progressors. The numbe r of nonsynonymous substitutions was not associated with virus load or virus phenotype, which are established predictors of disease progress ion, but correlated strongly with the duration of the immunocompetent period (r(2) = 0.41; P = 0.001). This indicates that there is no causa tive relationship between intrahost evolution and CD4(+) cell decline. Our data suggest that intrahost evolution in human immunodeficiency v irus type 1 infection is driven by selective forces, the strength of w hich is related to the duration of the immunocompetent period.