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 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% hadenvsequences 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.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Nina N
NN
Hosmane
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Kyungyoon J
KJ
Kwon
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Katherine M
KM
Bruner
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Adam A
AA
Capoferri
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Subul
0000-0003-1862-6012
S
Beg
Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032.
Daniel I S
DI
Rosenbloom
AIDS and Cancer Virus Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
Brandon F
BF
Keele
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Ya-Chi
YC
Ho
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Janet D
0000-0001-6712-3775
JD
Siliciano
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205 rsiliciano@jhmi.edu.|Howard Hughes Medical Institute, Baltimore, MD 21205.
Robert F
0000-0002-1764-1993
RF
Siliciano
D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D016679:Genome, Viral; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation; D014779:Virus Replication