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 D. Siliciano, Robert F. Siliciano

Research output: Research - peer-reviewArticle

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.

LanguageEnglish (US)
Pages959-972
Number of pages14
JournalJournal of Experimental Medicine
Volume214
Issue number4
DOIs
StatePublished - Apr 1 2017

Fingerprint

HIV-1
Cell Proliferation
T-Lymphocytes
Infection
Virus Release
Virus Replication
Mitogens
Cell Death
Genome
Viruses

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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

In: Journal of Experimental Medicine, Vol. 214, No. 4, 01.04.2017, p. 959-972.

Research output: Research - peer-reviewArticle

Hosmane NN, Kwon KJ, Bruner KM, Capoferri AA, Beg S, Rosenbloom DIS et al. Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1: Potential role in latent reservoir dynamics. Journal of Experimental Medicine. 2017 Apr 1;214(4):959-972. Available from, DOI: 10.1084/jem.20170193
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./ Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1 : Potential role in latent reservoir dynamics. In: Journal of Experimental Medicine. 2017 ; Vol. 214, No. 4. pp. 959-972
@article{1db824a5899744afa613b3685844f072,
title = "Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1: Potential role in latent reservoir dynamics",
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.",
author = "Hosmane, {Nina N.} and Kwon, {Kyungyoon J.} and Bruner, {Katherine M.} and Capoferri, {Adam A.} and Subul Beg and Rosenbloom, {Daniel I.S.} and Keele, {Brandon F.} and Ho, {Ya Chi} and Siliciano, {Janet D.} and Siliciano, {Robert F.}",
year = "2017",
month = "4",
doi = "10.1084/jem.20170193",
volume = "214",
pages = "959--972",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "4",

}

TY - JOUR

T1 - Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1

T2 - Journal of Experimental Medicine

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85019496327&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019496327&partnerID=8YFLogxK

U2 - 10.1084/jem.20170193

DO - 10.1084/jem.20170193

M3 - Article

VL - 214

SP - 959

EP - 972

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 4

ER -