Many HIV-infected children treated with protease inhibitors (PI) reconstitute immunity despite viral breakthrough predicting disease progression. We studied a unique cohort of PI treated children with advanced disease who demonstrated sustained CD4 T cell counts but median post therapy viral load rebounded to >4.0 log(10) copies/ml. Phylogenetic relationships between pre- and post-therapy viruses reveals significant bottlenecks for quasispecies with natural polymorphisms mapping outside of protease active site providing selective advantage for emergence. Among discordant subjects post-therapy viruses fell into two phenotypes; high viral loads (median >5.0 log(10) copies/ml) and attenuated post-therapy replication (median <4.0 log(10) copies/ml). Both groups showed similar degrees of CD4 T cell immune reconstitution and were similar to children who optimally suppressed virus to <400 copies/ml. Both high fit and low fit discordant response groups showed high reconstitution of naïve CD4 CD45RA T cells (median 388 and 357 cells/microl, respectively). Naïve T cells increases suggest virus replicating under PI selective pressure do not impair thymic output. If therapeutic options are limited, selection of therapy which allows immune reconstitution despite suboptimal viral control may be beneficial. This novel paradigm for virus/host interactions may lead to therapeutic approaches to attenuate viral pathogenesis.