TY - JOUR
T1 - The Landscape of Persistent Viral Genomes in ART-Treated SIV, SHIV, and HIV-2 Infections
AU - Bender, Alexandra M.
AU - Simonetti, Francesco R.
AU - Kumar, Mithra R.
AU - Fray, Emily J.
AU - Bruner, Katherine M.
AU - Timmons, Andrew E.
AU - Tai, Katherine Y.
AU - Jenike, Katharine M.
AU - Antar, Annukka A.R.
AU - Liu, Po Ting
AU - Ho, Ya Chi
AU - Raugi, Dana N.
AU - Seydi, Moussa
AU - Gottlieb, Geoffrey S.
AU - Okoye, Afam A.
AU - Del Prete, Gregory Q.
AU - Picker, Louis J.
AU - Mankowski, Joseph L.
AU - Lifson, Jeffrey D.
AU - Siliciano, Janet D.
AU - Laird, Greg M.
AU - Barouch, D. H.
AU - Clements, Janice E.
AU - Siliciano, Robert F.
N1 - Funding Information:
We thank Dr. Stephen Hughes (NCI) for valuable inputs. This work was supported by the NIH Martin Delaney I4C ( UM1 AI126603 ), Beat-HIV ( UM1 AI126620 ) and DARE ( UM1 AI12661 ) Collaboratories, the Howard Hughes Medical Institute , and the Bill and Melinda Gates Foundation ( OPP1115715 ) to R.F.S. Animal studies at Johns Hopkins were supported by NCRR and the Office of Research Infrastructure Programs (ORIP) of the NIH grant P40 OD013117 . Additional support for animal studies came from NIH grants PPG MH070306 , NS077869 , NS076357 , U19-0AI076113 , R56 AI118753 , 1R01AI127142 , and in part with federal funds from the National Cancer Institute , NIH contract HSN261200800001E . The authors thank Gilead and ViiV for providing antiretrovirals. The funders had no role in study design, data collection and interpretation, or publication. E.J.F. was supported by NIH T32 GM007445 . A.A.R.A. was supported by NIH T32 AI007291-27 . HIV-2 studies were supported by grants to G.S.G. from the NIH/NIAID ( AI120765 and AI060466 ). We thank the patients and staff of the UW-Senegal Research Collaboration ( http://www.uwsenegalresearch.com ).
Funding Information:
We thank Dr. Stephen Hughes (NCI) for valuable inputs. This work was supported by the NIH Martin Delaney I4C (UM1 AI126603), Beat-HIV (UM1 AI126620) and DARE (UM1 AI12661) Collaboratories, the Howard Hughes Medical Institute, and the Bill and Melinda Gates Foundation (OPP1115715) to R.F.S. Animal studies at Johns Hopkins were supported by NCRR and the Office of Research Infrastructure Programs (ORIP) of the NIH grant P40 OD013117. Additional support for animal studies came from NIH grants PPG MH070306, NS077869, NS076357, U19-0AI076113, R56 AI118753, 1R01AI127142, and in part with federal funds from the National Cancer Institute, NIH contract HSN261200800001E. The authors thank Gilead and ViiV for providing antiretrovirals. The funders had no role in study design, data collection and interpretation, or publication. E.J.F. was supported by NIH T32 GM007445. A.A.R.A. was supported by NIH T32 AI007291-27. HIV-2 studies were supported by grants to G.S.G. from the NIH/NIAID (AI120765 and AI060466). We thank the patients and staff of the UW-Senegal Research Collaboration (http://www.uwsenegalresearch.com). A.M.B. and R.F.S. designed the study. A.M.B. F.R.S. M.R.K. E.J.F. and K.M.J. performed the experiments. K.M.B. A.E.T. K.Y.T. A.A.R.A. Y.-C.H. G.M.L. and J.D.S. contributed to experimental design and data analysis. P.-T.L. A.A.O. G.Q.D.P. L.J.P. J.L.M. J.D.L. D.H.B. and J.E.C. provided NHP samples and expertise. D.N.R. M.S. and G.S.G. provided HIV-2 samples. A.M.B. and R.F.S. wrote the manuscript. Aspects of HIV-1 IPDA are subject of a patent application PCT/ US16/28822 filed by Johns Hopkins University. K.M.B. and R.F.S. are inventors on this application. Accelevir Diagnostics holds an exclusive license for this patent application. G.M.L. is an employee of and shareholder in Accelevir Diagnostics. R.F.S. holds no equity interest in Accelevir Diagnostics. R.F.S is a consultant on cure-related HIV research for Merck and AbbVie.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/7/10
Y1 - 2019/7/10
N2 - Evaluation of HIV cure strategies is complicated by defective proviruses that persist in ART-treated patients but are irrelevant to cure. Non-human primates (NHP) are essential for testing cure strategies. However, the persisting proviral landscape in ART-treated NHPs is uncharacterized. Here, we describe viral genomes persisting in ART-treated, simian immunodeficiency virus (SIV)-infected NHPs, simian-human immunodeficiency virus (SHIV)-infected NHPs, and humans infected with HIV-2, an SIV-related virus. The landscapes of persisting SIV, SHIV, and HIV-2 genomes are also dominated by defective sequences. However, there was a significantly higher fraction of intact SIV proviral genomes compared to ART-treated HIV-1 or HIV-2 infected humans. Compared to humans with HIV-1, SIV-infected NHPs had more hypermutated genomes, a relative paucity of clonal SIV sequences, and a lower frequency of deleted genomes. Finally, we report an assay for measuring intact SIV genomes which may have value in cure research. Understanding the proviral landscape in ART-treated non-human primates (NHP) is crucial before using them to test HIV cure strategies. Bender et al. report that while most proviruses persisting in ART-treated SIV-infected NHPs are defective, there is a significantly higher fraction of intact genomes compared to ART-treated HIV-1-infected humans.
AB - Evaluation of HIV cure strategies is complicated by defective proviruses that persist in ART-treated patients but are irrelevant to cure. Non-human primates (NHP) are essential for testing cure strategies. However, the persisting proviral landscape in ART-treated NHPs is uncharacterized. Here, we describe viral genomes persisting in ART-treated, simian immunodeficiency virus (SIV)-infected NHPs, simian-human immunodeficiency virus (SHIV)-infected NHPs, and humans infected with HIV-2, an SIV-related virus. The landscapes of persisting SIV, SHIV, and HIV-2 genomes are also dominated by defective sequences. However, there was a significantly higher fraction of intact SIV proviral genomes compared to ART-treated HIV-1 or HIV-2 infected humans. Compared to humans with HIV-1, SIV-infected NHPs had more hypermutated genomes, a relative paucity of clonal SIV sequences, and a lower frequency of deleted genomes. Finally, we report an assay for measuring intact SIV genomes which may have value in cure research. Understanding the proviral landscape in ART-treated non-human primates (NHP) is crucial before using them to test HIV cure strategies. Bender et al. report that while most proviruses persisting in ART-treated SIV-infected NHPs are defective, there is a significantly higher fraction of intact genomes compared to ART-treated HIV-1-infected humans.
KW - HIV-2
KW - SHIV
KW - SIV
KW - clonal expansion
KW - defective provirus
KW - latent reservoir
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U2 - 10.1016/j.chom.2019.06.005
DO - 10.1016/j.chom.2019.06.005
M3 - Article
C2 - 31295427
AN - SCOPUS:85068104375
SN - 1931-3128
VL - 26
SP - 73-85.e4
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 1
ER -