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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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.
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