Altered viral fitness of HIV-1 following failure of protease inhibitor-based therapy

HIV-1 isolated from patients with improved CD4(+) T-cell counts despite vir ologic failure on a nucleoside reverse transcriptase inhibitor (NRTI) and p rotease inhibitor (PI)-containing regimen were characterized. Five paired v irus isolates from patients before and after zidovudine, lamivudine, and ri tonavir treatment were tested. Human peripheral blood leukocyte-reconstitut ed severe combined immunodeficient (hu-PBL-SCID) mice were infected with pr e- or posttreatment isolates and plasma HIV-1 RNA levels and CD4(+) T cells were measured. Two of five post-treatment isolates exhibited decreased rep lication in hu-PBL-SCID mice compared with the paired pretreatment isolate, and both had the V82A mutation in protease associated with resistance to P I. One additional posttreatment isolate with the M184V mutation in reverse transcriptase showed diminished replication. CD4(+) T-cell depletion was si milar following infection with either the pre- or posttreatment isolates. S ubtle losses in the replication capacity of PI- or NRTI-resistant viruses m ay contribute to relative preservation of CD4(+) T-cell counts in persons w ho 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.