HIV-1 Integration Landscape during Latent and Active Infection

• Published in: Cell Vol. 160; no. 3; pp. 420 - 432
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.01.2015
• Subjects: Alu Elements; antiretroviral agents; CD4-positive T-lymphocytes; CD4-Positive T-Lymphocytes - virology; Clone Cells; clones; controllers; Defective Viruses - genetics; Defective Viruses - physiology; genome; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - genetics; HIV-1 - physiology; Human immunodeficiency virus 1; Humans; Immunologic Memory; landscapes; proviruses; Proviruses - physiology; Single-Cell Analysis; therapeutics; Virus Integration; Virus Latency
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2015.01.020

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.