Persistent HIV-1 replication maintains the tissue reservoir during therapy

Ramon Lorenzo-Redondo; Helen R. Fryer; Trevor Bedford; Eun Young Kim; John Archer; Sergei L. Kosakovsky Pond; Yoon Seok Chung; Sudhir Penugonda; Jeffrey G. Chipman; Courtney V. Fletcher; Timothy W. Schacker; Michael H. Malim; Andrew Rambaut; Ashley T. Haase; Angela R. McLean; Steven M. Wolinsky

doi:10.1038/nature16933

Persistent HIV-1 replication maintains the tissue reservoir during therapy

Ramon Lorenzo-Redondo, Helen R. Fryer, Trevor Bedford, Eun Young Kim, John Archer, Sergei L. Kosakovsky Pond, Yoon Seok Chung, Sudhir Penugonda, Jeffrey G. Chipman, Courtney V. Fletcher, Timothy W. Schacker, Michael H. Malim, Andrew Rambaut, Ashley T. Haase, Angela R. McLean, Steven M. Wolinsky

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Abstract

Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy.

Original language	English (US)
Pages (from-to)	51-56
Number of pages	6
Journal	Nature
Volume	530
Issue number	7588
DOIs	https://doi.org/10.1038/nature16933
State	Published - Feb 4 2016

Bibliographical note

Funding Information:
Acknowledgements We thank G. J. Beilman, A. Thorkelson, P. Swantek, K. Mars and K. Kunstman for their technical assistance. We thank E. Domingo and T. Bhattacharya for their constructive and informed review. We are indebted to the patients who participated in this study. This work was supported by the National Institutes of Health (DA033773 to S.M.W., AI1074340 to T.W.S., and GM110749 to S.L.K.P.), the Medical Research Council (G1000196 to M.H.M.), the Framework Programme for Research and Technological Development (278433-PREDEMICS to A.R.) and the European Research Council (260864 to A.R.). The Oxford Martin School supports H.R.F. All Souls College supports A.R.M. where S.M.W. held a Visiting Fellowship. A Newton International Fellowship from the Royal Society supported T.B. A Wellcome Trust Investigator award supported M.H.M. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2016 Macmillan Publishers Limited. All rights reserved.

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Lorenzo-Redondo, R., Fryer, H. R., Bedford, T., Kim, E. Y., Archer, J., Kosakovsky Pond, S. L., Chung, Y. S., Penugonda, S., Chipman, J. G., Fletcher, C. V., Schacker, T. W., Malim, M. H., Rambaut, A., Haase, A. T., McLean, A. R., & Wolinsky, S. M. (2016). Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature, 530(7588), 51-56. https://doi.org/10.1038/nature16933

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title = "Persistent HIV-1 replication maintains the tissue reservoir during therapy",

abstract = "Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy.",

author = "Ramon Lorenzo-Redondo and Fryer, {Helen R.} and Trevor Bedford and Kim, {Eun Young} and John Archer and {Kosakovsky Pond}, {Sergei L.} and Chung, {Yoon Seok} and Sudhir Penugonda and Chipman, {Jeffrey G.} and Fletcher, {Courtney V.} and Schacker, {Timothy W.} and Malim, {Michael H.} and Andrew Rambaut and Haase, {Ashley T.} and McLean, {Angela R.} and Wolinsky, {Steven M.}",

note = "Funding Information: Acknowledgements We thank G. J. Beilman, A. Thorkelson, P. Swantek, K. Mars and K. Kunstman for their technical assistance. We thank E. Domingo and T. Bhattacharya for their constructive and informed review. We are indebted to the patients who participated in this study. This work was supported by the National Institutes of Health (DA033773 to S.M.W., AI1074340 to T.W.S., and GM110749 to S.L.K.P.), the Medical Research Council (G1000196 to M.H.M.), the Framework Programme for Research and Technological Development (278433-PREDEMICS to A.R.) and the European Research Council (260864 to A.R.). The Oxford Martin School supports H.R.F. All Souls College supports A.R.M. where S.M.W. held a Visiting Fellowship. A Newton International Fellowship from the Royal Society supported T.B. A Wellcome Trust Investigator award supported M.H.M. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited. All rights reserved.",

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AU - Lorenzo-Redondo, Ramon

AU - Fryer, Helen R.

AU - Bedford, Trevor

AU - Kim, Eun Young

AU - Archer, John

AU - Kosakovsky Pond, Sergei L.

AU - Chung, Yoon Seok

AU - Penugonda, Sudhir

AU - Chipman, Jeffrey G.

AU - Fletcher, Courtney V.

AU - Schacker, Timothy W.

AU - Malim, Michael H.

AU - Rambaut, Andrew

AU - Haase, Ashley T.

AU - McLean, Angela R.

AU - Wolinsky, Steven M.

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N2 - Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy.

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Persistent HIV-1 replication maintains the tissue reservoir during therapy

Abstract

Bibliographical note

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