HIV-1 integration landscape during latent and active infection

Lillian B Cohn; Israel T Silva; Thiago Y Oliveira; Rafael A Rosales; Erica H Parrish; Gerald H Learn; Beatrice H Hahn; Julie L Czartoski; M Juliana McElrath; Clara Lehmann; Florian Klein; Marina Caskey; Bruce D Walker; Janet D Siliciano; Robert F Siliciano; Mila Jankovic; Michel C Nussenzweig

doi:10.1016/j.cell.2015.01.020

HIV-1 integration landscape during latent and active infection

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

Authors

Lillian B Cohn¹, Israel T Silva², Thiago Y Oliveira¹, Rafael A Rosales³, Erica H Parrish⁴, Gerald H Learn⁴, Beatrice H Hahn⁴, Julie L Czartoski⁵, M Juliana McElrath⁵, Clara Lehmann⁶, Florian Klein¹, Marina Caskey¹, Bruce D Walker⁷, Janet D Siliciano⁸, Robert F Siliciano⁹, Mila Jankovic¹, Michel C Nussenzweig¹⁰

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alu Elements
CD4-Positive T-Lymphocytes / virology*
Clone Cells
Defective Viruses / genetics
Defective Viruses / physiology
HIV Infections / drug therapy
HIV Infections / virology*
HIV-1 / genetics
HIV-1 / physiology*
Humans
Immunologic Memory
Proviruses / physiology
Single-Cell Analysis
Virus Integration*
Virus Latency*

Abstract

Publication types

MeSH terms

Grants and funding