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Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):E11341-E11348. doi: 10.1073/pnas.1813512115. Epub 2018 Nov 12.

Relationship between intact HIV-1 proviruses in circulating CD4+ T cells and rebound viruses emerging during treatment interruption.

Author information

1
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
2
Laboratory of Experimental Immunology, Institute of Virology, University Hospital Cologne, 50935 Cologne, Germany.
3
Department I of Internal Medicine, University Hospital Cologne, 50931 Cologne, Germany.
4
German Center for Infection Research, 50931 Cologne, Germany.
5
Department of Physics and Astronomy, University of California, Riverside, CA 92521.
6
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
7
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065; nussen@rockefeller.edu.
8
Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065.

Abstract

Combination antiretroviral therapy controls but does not cure HIV-1 infection because a small fraction of cells harbor latent viruses that can produce rebound viremia when therapy is interrupted. The circulating latent virus reservoir has been documented by a variety of methods, most prominently by viral outgrowth assays (VOAs) in which CD4+ T cells are activated to produce virus in vitro, or more recently by amplifying proviral near full-length (NFL) sequences from DNA. Analysis of samples obtained in clinical studies in which individuals underwent analytical treatment interruption (ATI), showed little if any overlap between circulating latent viruses obtained from outgrowth cultures and rebound viruses from plasma. To determine whether intact proviruses amplified from DNA are more closely related to rebound viruses than those obtained from VOAs, we assayed 12 individuals who underwent ATI after infusion of a combination of two monoclonal anti-HIV-1 antibodies. A total of 435 intact proviruses obtained by NFL sequencing were compared with 650 latent viruses from VOAs and 246 plasma rebound viruses. Although, intact NFL and outgrowth culture sequences showed similar levels of stability and diversity with 39% overlap, the size of the reservoir estimated from NFL sequencing was larger than and did not correlate with VOAs. Finally, intact proviruses documented by NFL sequencing showed no sequence overlap with rebound viruses; however, they appear to contribute to recombinant viruses found in plasma during rebound.

KEYWORDS:

HIV; analytical treatment interruption; latent reservoir; sequencing

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