TY - JOUR
T1 - Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1
T2 - Potential role in latent reservoir dynamics
AU - Hosmane, Nina N.
AU - Kwon, Kyungyoon J.
AU - Bruner, Katherine M.
AU - Capoferri, Adam A.
AU - Beg, Subul
AU - Rosenbloom, Daniel I.S.
AU - Keele, Brandon F.
AU - Ho, Ya Chi
AU - Siliciano, Janet D.
AU - Siliciano, Robert F.
N1 - Funding Information:
This work was supported by the Martin Delaney DARE, I4C, and BEAT-HIV Collaboratories (National Institutes of Health grants UM1AI126611, UM1AI126603, and UM1AI126620), by an American Foundation for Aids Research (amfAR) Consortium on HIV Eradication Collaborative Research Grant (108165-50-RGRL), by the Johns Hopkins Center for AIDS Research (P30AI094189), by the National Institutes of Health (grant 43222), and by the Howard Hughes Medical Institute, the Bill and Melinda Gates Foundation (grant OPP1115715), and in part with Federal funds from the National Cancer Institute, National Institutes of Health (contract HHSN261200800001E). D.I.S.R. acknowledges support from an amfAR fellowship (109511-61-RKRL).The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The authors declare no competing financial interests.
Publisher Copyright:
© 2017 Hosmane et al.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20170193
DO - 10.1084/jem.20170193
M3 - Article
C2 - 28341641
AN - SCOPUS:85019496327
VL - 214
SP - 959
EP - 972
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 4
ER -