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

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 producti...

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Bibliographic Details
Published in:The Journal of experimental medicine 2017-04, Vol.214 (4), p.959-972
Main Authors: Hosmane, Nina N, Kwon, Kyungyoon J, Bruner, Katherine M, Capoferri, Adam A, Beg, Subul, Rosenbloom, Daniel I S, Keele, Brandon F, Ho, Ya-Chi, Siliciano, Janet D, Siliciano, Robert F
Format: Article
Language:English
Subjects:
Antiretroviral agents
Antiretroviral therapy
CD4 antigen
CD4-Positive T-Lymphocytes - virology
Cell activation
Cell death
Cell growth
Cell proliferation
Gene sequencing
Genome, Viral
Genomes
HIV
HIV-1 - genetics
HIV-1 - physiology
Human immunodeficiency virus
Humans
In vivo methods and tests
Infections
Latency
Latent infection
Lymphocyte Activation
Lymphocytes
Lymphocytes T
Mitogens
Phylogeny
Progeny
Replication
Statistical analysis
Virus Replication
Viruses
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Summary: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 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.
ISSN:0022-1007
1540-9538
1540-9538
DOI:10.1084/jem.20170193