The evolution of human immunodeficiency virus type 1 (HIV-1) env gp120 region was addressed in HIV-1 infected children showing virological failure to antiretroviral therapy (ART). Sequence analysis of the replicating plasma virus at baseline and after one year of therapy documented evolution of gp120 in all subjects but one. Analysis of the host's selective pressure showed that the values of Ka/Ks ratios were higher in the V3 sequence than in the whole C2-V5 region in 4 of 5 children with improvement of thymic output. Moreover, in 2 of the 4 chidren, the V3 evolution paralleled with a reverse shift of the viral phenotype (from CXCR4-tropic to CCR5-tropic). These results suggest that, under ART, the V3 evolution towards less pathogenic viral variants may be driven by the host's increased selective pressure following restoration of thymic function and immune reconstitution.