Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1: Potential role in latent reservoir dynamics

Nina N. Hosmane, Kyungyoon J. Kwon, Katherine M. Bruner, Adam A. Capoferri, Subul Beg, Daniel I.S. Rosenbloom, Brandon F. Keele, Ya Chi Ho, Janet M Siliciano, Robert F Siliciano

Research output: Contribution to journalArticle

Abstract

A latent reservoir for HIV-1 in resting CD4+ T lymphocytes precludes cure. Mechanisms underlying reservoir stability are unclear. Recent studies suggest an unexpected degree of infected cell proliferation in vivo. T cell activation drives proliferation but also reverses latency, resulting in productive infection that generally leads to cell death. In this study, we show that latently infected cells can proliferate in response to mitogens without producing virus, generating progeny cells that can release infectious virus. Thus, assays relying on one round of activation underestimate reservoir size. Sequencing of independent clonal isolates of replication-competent virus revealed that 57% had env sequences identical to other isolates from the same patient. Identity was confirmed by full-genome sequencing and was not attributable to limited viral diversity. Phylogenetic and statistical analysis suggested that identical sequences arose from in vivo proliferation of infected cells, rather than infection of multiple cells by a dominant viral species. The possibility that much of the reservoir arises by cell proliferation presents challenges to cure.

Original languageEnglish (US)
Pages (from-to)959-972
Number of pages14
JournalJournal of Experimental Medicine
Volume214
Issue number4
DOIs
StatePublished - Apr 1 2017

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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