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 language | English (US) |
|---|---|
| Pages (from-to) | 959-972 |
| Number of pages | 14 |
| Journal | Journal of Experimental Medicine |
| Volume | 214 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 1 2017 |
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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: Contribution to journal › Article
}
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.
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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 -