Abstract:The barrier to curing HIV-1 is thought to reside primarily in CD4(+) Tcells containing silent proviruses. To characterize these latently infected cells, we studied the integration profile of HIV-1 in viremic progressors, individuals receiving antiretroviral therapy, and viremic controllers. Clonally expanded Tcells represented the majority of all integrations and increased during therapy. However, none of the 75 expanded Tcell clones assayed contained intact virus. In contrast, the cells bearing single integration events decreased in frequency over time on therapy, and the surviving cells were enriched for HIV-1 integration in silent regions of the genome. Finally, there was a strong preference for integration into, or in close proximity to, Alu repeats, which were also enriched in local hotspots for integration. The data indicate that dividing clonally expanded Tcells contain defective proviruses and that the replication-competent reservoir is primarily found in CD4(+) Tcells that remain relatively quiescent.
