Evolution of human immunodeficiency virus type 1 in relation to disease progression in children

Objective: To compare patterns of nonsynonymous and synonymous substitutions over time in the V1V2 and C2V3 regions of human immunodeficiency virus type 1 (HIV-1) env and in a conserved segment of pol in HIV-1-infected children with varying rates of CD4⁺ T-cell decline. Study Design/Methods: Longitudinal study of HIV-1 genetic variants sampled from peripheral blood of 3 children affected with acquired immunodeficiency syndrome (AIDS) and 4 children with slow disease progression. Nested polymerase chain reaction (PCR) was used to detect HIV-1 genetic material in plasma-derived virions and cellular DNA. Sequence variants were enumerated by screening cloned PCR products using heteroduplex mobility assay (HMA) or single-strand conformation polymorphism analysis (SSCP) and nucleotide sequencing. Frequencies of nonsynonymous and synonymous substitutions within sampling points and the accumulation rate of nucleotide substitutions over the period of observation were calculated. Results: In the C2V3 region, higher rates of accumulation of nonsynonymous substitutions were associated with more precipitous declines in CD4⁺ cell numbers. In the V1V2 region, rates of accumulation of nonsynonymous substitutions were comparable with those in the C2V3 region, but similar rates were observed in AIDS-affected children and children with slow disease progression. The rate of accumulation of nonsynonymous substitutions in the pol region was lower than that in the C2V3 and V1V2 regions. Conclusions: Rates of accumulation of nucleotide substitutions vary across the HIV-1 genome and differ in relation to disease progression in children. The finding of greater rates of non-synonymous substitution in the immunodominant C2V3 region in children whose disease progressed rapidly is consistent with a vigorous but inadequate immune response in children who are unable to control HIV-1 infection.