Distinct viral reservoirs in individuals with spontaneous control of HIV-1

Chenyang Jiang, Xiaodong Lian, Ce Gao, Xiaoming Sun, Kevin B. Einkauf, Joshua M. Chevalier, Samantha M. Y. Chen, Stephane Hua, Ben Rhee, Kaylee Chang, Jane E. Blackmer, Matthew Osborn, Michael J. Peluso, Rebecca Hoh, Ma Somsouk, Jeffrey Milush, Lynn N. Bertagnolli, Sarah E. Sweet, Joseph A. Varriale, Peter D. Burbelo, Tae-Wook Chun, Gregory M. Laird, Erik Serrao, Alan N. Engelman, Mary Carrington, Robert F. Siliciano, Janet M. Siliciano, Steven G. Deeks, Bruce D. Walker, Mathias Lichterfeld and Xu G. Yu ()
Additional contact information
Chenyang Jiang: Ragon Institute of MGH, MIT and Harvard
Xiaodong Lian: Ragon Institute of MGH, MIT and Harvard
Ce Gao: Ragon Institute of MGH, MIT and Harvard
Xiaoming Sun: Ragon Institute of MGH, MIT and Harvard
Kevin B. Einkauf: Ragon Institute of MGH, MIT and Harvard
Joshua M. Chevalier: Ragon Institute of MGH, MIT and Harvard
Samantha M. Y. Chen: Ragon Institute of MGH, MIT and Harvard
Stephane Hua: Ragon Institute of MGH, MIT and Harvard
Ben Rhee: Ragon Institute of MGH, MIT and Harvard
Kaylee Chang: Ragon Institute of MGH, MIT and Harvard
Jane E. Blackmer: Ragon Institute of MGH, MIT and Harvard
Matthew Osborn: Ragon Institute of MGH, MIT and Harvard
Michael J. Peluso: University of California at San Francisco
Rebecca Hoh: University of California at San Francisco
Ma Somsouk: University of California at San Francisco
Jeffrey Milush: University of California at San Francisco
Lynn N. Bertagnolli: Johns Hopkins University School of Medicine
Sarah E. Sweet: Johns Hopkins University School of Medicine
Joseph A. Varriale: Johns Hopkins University School of Medicine
Peter D. Burbelo: Dental Clinical Research Core, National Institute of Dental and Craniofacial Research, National Institutes of Health
Tae-Wook Chun: National Institute of Allergies and Infectious Diseases
Gregory M. Laird: Accelevir Diagnostics
Erik Serrao: Dana-Farber Cancer Institute
Alan N. Engelman: Dana-Farber Cancer Institute
Mary Carrington: Ragon Institute of MGH, MIT and Harvard
Robert F. Siliciano: Johns Hopkins University School of Medicine
Janet M. Siliciano: Johns Hopkins University School of Medicine
Steven G. Deeks: University of California at San Francisco
Bruce D. Walker: Ragon Institute of MGH, MIT and Harvard
Mathias Lichterfeld: Ragon Institute of MGH, MIT and Harvard
Xu G. Yu: Ragon Institute of MGH, MIT and Harvard

Nature, 2020, vol. 585, issue 7824, 261-267

Abstract: Abstract Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected individuals (here termed ‘elite controllers’), despite the presence of a replication-competent viral reservoir1. Inducing such an ability to spontaneously maintain undetectable plasma viraemia is a major objective of HIV-1 cure research, but the characteristics of proviral reservoirs in elite controllers remain to be determined. Here, using next-generation sequencing of near-full-length single HIV-1 genomes and corresponding chromosomal integration sites, we show that the proviral reservoirs of elite controllers frequently consist of oligoclonal to near-monoclonal clusters of intact proviral sequences. In contrast to individuals treated with long-term antiretroviral therapy, intact proviral sequences from elite controllers were integrated at highly distinct sites in the human genome and were preferentially located in centromeric satellite DNA or in Krüppel-associated box domain-containing zinc finger genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, the integration sites of intact proviral sequences from elite controllers showed an increased distance to transcriptional start sites and accessible chromatin of the host genome and were enriched in repressive chromatin marks. These data suggest that a distinct configuration of the proviral reservoir represents a structural correlate of natural viral control, and that the quality, rather than the quantity, of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, in one elite controller, we were unable to detect intact proviral sequences despite analysing more than 1.5 billion peripheral blood mononuclear cells, which raises the possibility that a sterilizing cure of HIV-1 infection, which has previously been observed only following allogeneic haematopoietic stem cell transplantation2,3, may be feasible in rare instances.

Date: 2020
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DOI: 10.1038/s41586-020-2651-8

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