Evidence for positive selection driving the evolution of HIV-1 env under potent antiviral therapy

In HIV-infected individuals treated with potent antiretroviral therapy, via ble virus can be isolated from latently infected cells several years into t herapy, due to the long life of these cells, ongoing replication replenishi ng this population, or both. We have analysed the Vs region of the HIV-1 en v gene isolated from six patients who have undergone 2 years of potent anti retroviral therapy without frank failure of viral suppression. We show that in two (and possibly three) patients, the sequence changes between baselin e virus and virus isolated from infected cells persisting 2 years into infe ction result from positive selection driving adaptive evolution, occurring either prior to or during therapy. Our analyses suggest low-level replicati on despite absence of drug resistance due to drug sanctuary sites, or to lo w-level ongoing replication in the presence of alterations in the selective environment during therapy, perhaps due to a decline in HIV-specific immun e responsiveness or changes in target cell pools. In one patient, genetic d ivergence between baseline plasma and infected cells isolated during therap y may reflect the long half-life of some of these persistent cell populatio ns and the divergence of viral subpopulations that occurred prior to therap y. (C) 2001 Academic Press.