HIV-1 isolated from patients with improved CD4+ T-cell counts despite virologic failure on a nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI)-containing regimen were characterized. Five paired virus isolates from patients before and after zidovudine, lamivudine, and ritonavir treatment were tested. Human peripheral blood leukocyte-reconstituted severe combined immunodeficient (hu-PBL-SCID) mice were infected with pre-or posttreatment isolates and plasma HIV-1 RNA levels and CD4+ T cells were measured. Two of five post-treatment isolates exhibited decreased replication in hu-PBL-SCID mice compared with the paired pretreatment isolate, and both had the V82A mutation in protease associated with resistance to PI. One additional posttreatment isolate with the M184V mutation in reverse transcriptase showed diminished replication. CD4+ T-cell depletion was similar following infection with either the pre-or posttreatment isolates. Subtle losses in the replication capacity of PI-or NRTI-resistant viruses may contribute to relative preservation of CD4+ T-cell counts in persons who experience virologic failure. Cytopathic effects of viral infection for target T cells vary from patient to patient but appear not to be influenced by mutations associated with failure of therapy in this system.