EVOLUTION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 IN PERINATALLY INFECTED INFANTS WITH RAPID AND SLOW PROGRESSION TO DISEASE

We addressed the relationship between the origin and evolution of huma n immunodeficiency virus type 1 (HIV-1) variants and disease outcome i n perinatally infected infants by studying the V3 regions of viral var iants in samples obtained from five transmitting mothers at delivery a nd obtained sequentially over the first year of life from their infect ed infants, two of whom (rapid progressors) rapidly progressed to havi ng AIDS. Phylogenetic analyses disclosed that the V3 sequences from ea ch mother-infant pair clustered together and were clearly distinct fro m those of the other pairs, Within each pair, the child's sequences fo rmed a monophyletic group, indicating that a single variant initiated the infection in both rapid and slow progressors. Plasma HIV-1 RNA lev els increased in all five infants during their first months of life an d then declined within the first semester of life only in the three sl ow progressors. V3 variability increased over time in all infants, but no differences in the pattern of V3 evolution in terms of potential v iral phenotype were observed, The numbers of synonymous and nonsynonym ous substitutions varied during the first semester of life regardless of viral load, CD4(+)-cell count, and disease progression, Conversely, during the second semester of life the rate of nonsynonymous substitu tions was higher than that of synonymous substitutions in the slow pro gressors but not in the rapid progressors, thus suggesting a stronger host selective pressure in the former. In view of the proposal that V3 genetic evolution is driven mainly by host immune constraints, these findings suggest that while the immune response to V3 might contribute to regulating viral levels after the first semester of life, it is un likely to play a determinant role in the initial viral decline soon af ter birth.