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Cell. 2015 Jan 29;160(3):420-32. doi: 10.1016/j.cell.2015.01.020.

HIV-1 integration landscape during latent and active infection.

Author information

1
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
2
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; National Institute of Science and Technology in Stem Cell and Cell Therapy and Center for Cell Based Therapy, Rua Catão Roxo, 2501, Ribeirão Preto CEP 14051-140, Brazil.
3
Departamento de Computação e Matemática, Universidade de São Paulo. Av. Bandeirantes, 3900, Ribeirão Preto CEP 14049-901, Brazil.
4
Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
6
Department I of Internal Medicine, University Hospital of Cologne, 50924 Cologne, Germany; German Centre for Infection Research, partner site Bonn-Cologne, 50924 Cologne, Germany.
7
Ragon Institute of MGH, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
8
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
9
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
10
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: nussen@rockefeller.edu.

Abstract

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.

PMID:
25635456
PMCID:
PMC4371550
DOI:
10.1016/j.cell.2015.01.020
[Indexed for MEDLINE]
Free PMC Article
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