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HIV-1 Viremia Not Suppressible By Antiretroviral Therapy Can Originate from Large T-Cell Clones Producing Infectious Virus

Elias K. Halvas, Kevin W. Joseph, Leah D. Brandt, Shuang Guo, Michele D. Sobolewski, Jana L. Jacobs, Camille Tumiotto, John K. Bui, Joshua C. Cyktor, Brandon F. Keele, Gene D. Morse, Michael J. Bale, Mary F. Kearney, John M. Coffin, Jason W. Rausch, Xiaolin Wu, Stephen H. Hughes, John W. Mellors
doi: https://doi.org/10.1101/2020.01.30.924159
Elias K. Halvas
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA (E.K.H., K.W.J., L.D.B., M.D.S., J.L.J., C.T., J.C.C, J.W.M)
Ph.D.
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Kevin W. Joseph
B.S.
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Leah D. Brandt
Ph.D.
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Shuang Guo
Ph.D.
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Michele D. Sobolewski
M.S.
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Jana L. Jacobs
Ph.D.
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Camille Tumiotto
M.D. Ph.D.
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John K. Bui
M.D.
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Joshua C. Cyktor
Ph.D.
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Brandon F. Keele
Ph.D.
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Gene D. Morse
Pharm.D.
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Michael J. Bale
B.S.
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Mary F. Kearney
Ph.D.
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John M. Coffin
Ph.D.
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Jason W. Rausch
Ph.D.
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Xiaolin Wu
Ph.D.
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Stephen H. Hughes
Ph.D.
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John W. Mellors
M.D.
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  • For correspondence: jwm1@pitt.edu
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Abstract

BACKGROUND HIV-1 viremia that is not suppressed by combination antiretroviral therapy (ART) is generally attributed to incomplete medication adherence and/or drug resistance. We evaluated individuals referred for non-suppressible viremia (plasma HIV-1 RNA above 40 copies/ml) who reported adherence to ART and did not show drug resistance to their current regimen.

METHODS Samples were collected from at least two time points from eight donors who had non-suppressible viremia for more than six months on ART. Single templates of HIV-1 RNA obtained from plasma and viral outgrowth of cultured cells and from proviral DNA were PCR-amplified and sequenced for evidence of clones of cells that produced infectious viruses. Clones were identified by host-proviral integration site analysis.

RESULTS HIV-1 genomic RNAs with identical sequences were identified in plasma samples from all eight donors. The identical viral RNA sequences did not change over time and lacked resistance to the ART regimen. In four of the donors, viral RNA sequences obtained from plasma matched those sequences from viral outgrowth cultures, indicating that the viruses were replication-competent. Integration sites for infectious proviruses from those four donors were mapped to introns of the MATR3, ZNF268, ZNF721/ABCA11P, and ABCA11P genes. The sizes of the clones were from 50 million to 350 million cells.

CONCLUSION Clones of HIV-1-infected cells producing virus can cause failure of ART to suppress viremia despite medication adherence and absence of drug resistance. The mechanisms involved in clonal expansion and persistence need to be defined to eliminate viremia and the HIV-1 reservoir.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 31, 2020.
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HIV-1 Viremia Not Suppressible By Antiretroviral Therapy Can Originate from Large T-Cell Clones Producing Infectious Virus
Elias K. Halvas, Kevin W. Joseph, Leah D. Brandt, Shuang Guo, Michele D. Sobolewski, Jana L. Jacobs, Camille Tumiotto, John K. Bui, Joshua C. Cyktor, Brandon F. Keele, Gene D. Morse, Michael J. Bale, Mary F. Kearney, John M. Coffin, Jason W. Rausch, Xiaolin Wu, Stephen H. Hughes, John W. Mellors
bioRxiv 2020.01.30.924159; doi: https://doi.org/10.1101/2020.01.30.924159
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HIV-1 Viremia Not Suppressible By Antiretroviral Therapy Can Originate from Large T-Cell Clones Producing Infectious Virus
Elias K. Halvas, Kevin W. Joseph, Leah D. Brandt, Shuang Guo, Michele D. Sobolewski, Jana L. Jacobs, Camille Tumiotto, John K. Bui, Joshua C. Cyktor, Brandon F. Keele, Gene D. Morse, Michael J. Bale, Mary F. Kearney, John M. Coffin, Jason W. Rausch, Xiaolin Wu, Stephen H. Hughes, John W. Mellors
bioRxiv 2020.01.30.924159; doi: https://doi.org/10.1101/2020.01.30.924159

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