EVOLUTION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ENV SEQUENCE VARIATION IN PATIENTS WITH DIVERSE RATES OF DISEASE PROGRESSION AND T-CELL FUNCTION

We examined the relationship between env sequence variation and diseas e progression in 10 human immunodeficiency virus type 1 (HIV-1)-seropo sitive subjects selected from a longitudinal cohort receiving zidovudi ne therapy. Five subjects were chosen for stable clinical status and C D4 counts (slow progressors), and five were selected for rapid clinica l deterioration and CD4 count decline (rapid progressors). The slow pr ogressors had significantly lower plasma viral RNA loads and greater l ymphoproliferative responses to mitogens than the rapid progressors. D NA sequences representing the C1 through C3 regions of env were amplif ied from two peripheral blood mononuclear cell DNA samples from each s ubject separated by an average of 2.5 years. Molecular clones of these amplicons were then sequenced, and DNA sequence and deduced amino aci d sequence distances were compared. Inter-time point sequence comparis on showed a higher rate of sequence evolution for the rapid progressor s in three of five matched pairs of rapid progressors and slow progres sors and for the slow progressors in the remaining two subject pairs. However, intra-time point sequence comparisons showed that four of fiv e slow progressors developed a more diverse quasispecies over time and one showed no change. In contrast, four of five rapid progressors sho wed no change in quasispecies diversity over time and one showed a sig nificant decrease in diversity. The overall C1 through C3 region quasi species diversity in the slow progressors at baseline was lower than t hat for the rapid progressors, but this difference was not significant at the follow-up time points. These diversity relationships were obsc ured if sequence analyses were limited to the 300-bp C2 to V3 region. Thus, HIV-1 quasispecies diversity increased over time in subjects wit h more functional immune systems.