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Cohn, Lillian B.; Silva, Israel T.; Oliveira, Thiago Y.; Rosales, Rafael A.; Parrish, Erica H.; Learn, Gerald H.; Hahn, Beatrice H.; Czartoski, Julie L.; McElrath, M. Juliana; Lehmann, Clara; Klein, Florian; Caskey, Marina; Walker, Bruce D.; Siliciano, Janet D.; Siliciano, Robert F.; Jankovic, Mila; Nussenzweig, Michel C.
Cell, 01/2015, Letnik: 160, Številka: 3Journal Article
The barrier to curing HIV-1 is thought to reside primarily in CD4+ T cells 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 T cells represented the majority of all integrations and increased during therapy. However, none of the 75 expanded T cell 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 T cells contain defective proviruses and that the replication-competent reservoir is primarily found in CD4+ T cells that remain relatively quiescent. Display omitted •Integration sequencing identifies clonally expanded and single HIV-1 integrations in human subjects•Large clonal families of HIV-1+ cells are likely not part of the latent reservoir•HIV-1 integrates near or into a 30 bp INT-motif found in Alu repeats HIV-1-infected CD4+ T cells that undergo clonal expansion are able to proliferate because their proviruses are defective. Conversely, the replication-competent reservoir is likely found in the subset of CD4+ T cells that carry unique integrations and remain quiescent.
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