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It remains controversial whether current antiretroviral therapy (ART) fully suppresses the cycles of HIV replication and viral evolution in vivo. If replication persists in sanctuary sites such as the lymph nodes, a high priority should be placed on improving ART regimes to target these sites. To investigate the question of ongoing viral replication on current ART regimens, we analyzed HIV populations in longitudinal samples from 10 HIV-1-infected children who initiated ART when viral diversity was low. Eight children started ART at less than ten months of age and showed suppression of plasma viremia for seven to nine years. Two children had uncontrolled viremia for fifteen and thirty months, respectively, before viremia suppression, and served as positive controls for HIV replication and evolution. These latter 2 children showed clear evidence of virus evolution, whereas multiple methods of analysis bore no evidence of virus evolution in any of the 8 children with viremia suppression on ART. Phylogenetic trees simulated with the recently reported evolutionary rate of HIV-1 on ART of 6 × 10-4 substitutions/site/ month bore no resemblance to the observed data. Taken together, these data refute the concept that ongoing HIV replication is common with ART and is the major barrier to curing HIV-1 infection.
Introduction
Antiretroviral therapy (ART) is known to suppress viremia and prolong survival of HIV-1-infected individuals but does not eliminate the HIV reservoirs that cause viral rebound after treatment is stopped. There has been continued debate about whether the HIV reservoir is maintained through the persistence and proliferation of cells infected before the initiation of ART (1-5), or from ongoing viral replication in potential ART sanctuary sites, such as lymph nodes (LNs) (6-10), with subsequent trafficking of recently infected cells into the blood (10, 11). If ongoing replication in tissues maintains the HIV reservoir, then preventing infection of new cells by developing antiretrovirals that better penetrate sanctuary sites such as LNs would be a high priority. Conversely, if current ART is fully effective at blocking full cycles of viral replication in both tissues and blood, then the elimination of proliferating and long-lived infected cells would be the highest priority for achieving an HIV-1 cure. It is therefore critical that the efficacy of current ART be fully understood to identify the...