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      HIV-1 variants are archived throughout infection and persist in the reservoir

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The HIV-1 reservoir consists of latently infected cells that persist despite antiretroviral therapy (ART). Elucidating the proviral genetic composition of the reservoir, particularly in the context of pre-therapy viral diversity, is therefore important to understanding reservoir formation and the persistence of latently infected cells. Here we investigate reservoir proviral variants from 13 Zambian acutely-infected individuals with additional pre-therapy sampling for a unique comparison to the ART-naïve quasispecies. We identified complete transmitted/founder (TF) viruses from seroconversion plasma samples, and additionally amplified and sequenced HIV-1 from plasma obtained one year post-infection and just prior to ART initiation. While the majority of proviral variants in the reservoir were most closely related to viral variants from the latest pre-therapy time point, we also identified reservoir proviral variants dating to or near the time of infection, and to intermediate time points between infection and treatment initiation. Reservoir proviral variants differing by five or fewer nucleotide changes from the TF virus persisted during treatment in five individuals, including proviral variants that exactly matched the TF in two individuals, one of whom had remained ART-naïve for more than six years. Proviral variants during treatment were significantly less divergent from the TF virus than plasma variants present at the last ART-naïve time point. These findings indicate that reservoir proviral variants are archived throughout infection, recapitulating much of the viral diversity that arises throughout untreated HIV-1 infection, and strategies to target and reduce the reservoir must therefore permit for the clearance of proviruses encompassing this extensive diversity.

          Author summary

          Despite reducing viremia to levels below the limit of detection in standard assays, effective antiretroviral therapy (ART) does not eradicate cells latently infected with HIV-1. These cells serve as a reservoir for viral rebound if therapy is interrupted; thus, understanding the composition of the reservoir may yield further targets for HIV-1 cure strategies. We have taken a genetic approach to elucidating the reservoir in 13 Zambian subtype C seroconvertors who were followed longitudinally through ART initiation and virologic suppression. In five of the 13 individuals, provirus sequences identical to or differing by five or fewer nucleotides from the transmitted/founder virus were detected, indicating archiving and persistence of early infection variants for more than six years following infection. While the majority of proviral variants in latently infected cells were most closely related to plasma virus circulating immediately prior to treatment initiation, additional variants dating to intermediate time points in the infection were also observed. These findings demonstrate that virus is archived during all stages of ART-naïve infection, and these variants persist throughout ART. HIV-1 cure strategies to eliminate the reservoir must address the broad genetic diversity of a within-host proviral quasispecies including variants archived from acute through chronic infection.

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          Most cited references 32

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          Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy.

          The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir for human immunodeficiency virus-type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined. In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harboring latent HIV-1 was low, 0.2 to 16.4 per 10(6) cells, and, in cross-sectional analysis, did not decrease with increasing time on therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs. This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment in patients who respond to HAART.
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            Choosing appropriate substitution models for the phylogenetic analysis of protein-coding sequences.

            Although phylogenetic inference of protein-coding sequences continues to dominate the literature, few analyses incorporate evolutionary models that consider the genetic code. This problem is exacerbated by the exclusion of codon-based models from commonly employed model selection techniques, presumably due to the computational cost associated with codon models. We investigated an efficient alternative to standard nucleotide substitution models, in which codon position (CP) is incorporated into the model. We determined the most appropriate model for alignments of 177 RNA virus genes and 106 yeast genes, using 11 substitution models including one codon model and four CP models. The majority of analyzed gene alignments are best described by CP substitution models, rather than by standard nucleotide models, and without the computational cost of full codon models. These results have significant implications for phylogenetic inference of coding sequences as they make it clear that substitution models incorporating CPs not only are a computationally realistic alternative to standard models but may also frequently be statistically superior.
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              Smooth skyride through a rough skyline: Bayesian coalescent-based inference of population dynamics.

              Kingman's coalescent process opens the door for estimation of population genetics model parameters from molecular sequences. One paramount parameter of interest is the effective population size. Temporal variation of this quantity characterizes the demographic history of a population. Because researchers are rarely able to choose a priori a deterministic model describing effective population size dynamics for data at hand, nonparametric curve-fitting methods based on multiple change-point (MCP) models have been developed. We propose an alternative to change-point modeling that exploits Gaussian Markov random fields to achieve temporal smoothing of the effective population size in a Bayesian framework. The main advantage of our approach is that, in contrast to MCP models, the explicit temporal smoothing does not require strong prior decisions. To approximate the posterior distribution of the population dynamics, we use efficient, fast mixing Markov chain Monte Carlo algorithms designed for highly structured Gaussian models. In a simulation study, we demonstrate that the proposed temporal smoothing method, named Bayesian skyride, successfully recovers "true" population size trajectories in all simulation scenarios and competes well with the MCP approaches without evoking strong prior assumptions. We apply our Bayesian skyride method to 2 real data sets. We analyze sequences of hepatitis C virus contemporaneously sampled in Egypt, reproducing all key known aspects of the viral population dynamics. Next, we estimate the demographic histories of human influenza A hemagglutinin sequences, serially sampled throughout 3 flu seasons.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: Data curationRole: Software
                Role: Data curationRole: SoftwareRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Funding acquisitionRole: Resources
                Role: Data curationRole: Funding acquisitionRole: Resources
                Role: Funding acquisitionRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Funding acquisitionRole: Resources
                Role: Funding acquisitionRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                3 June 2020
                June 2020
                : 16
                : 6
                Affiliations
                [1 ] Emory Vaccine Center, Emory University, Atlanta, Georgia, United States of America
                [2 ] British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
                [3 ] Human Immunology Lab, International AIDS Vaccine Initiative, London, England, United Kingdom
                [4 ] Zambia-Emory HIV Research Project, Lusaka, Zambia
                [5 ] Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
                [6 ] Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America
                [7 ] Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
                Vaccine Research Center, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                [¤a]

                Current address: Department of Biology, Emory University, Atlanta, Georgia, United States of America

                [¤b]

                Current address: Ragon Institute of MGH, MIT & Harvard, Cambridge, Massachusetts, United States of America

                Article
                PPATHOGENS-D-19-01625
                10.1371/journal.ppat.1008378
                7295247
                32492044
                © 2020 Brooks et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 7, Tables: 1, Pages: 22
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: 5F31AI122926-03
                Award Recipient :
                The research reported in this publication was funded in part by: NIH R01 AI064060 (E.H.), NIH R01 AI051231 (E.H.), NIH R21 AI127029 (J.B.J/ Z.L.B.), NIH UM1 AI126617 (Z.L.B.), NIH F31 AI122926 (K.B.), and the Yerkes National Primate Research Center base grant through the Office of Research Infrastructure Programs/OD P51OD11132. This work was also funded in part by the International AIDS Vaccine Initiative (IAVI) and made possible by the support of many donors, including the United States Agency for International Development (USAID). The full list of IAVI donors is available at http://www.iavi.org. The contents of this manuscript are the responsibility of the authors and do not necessarily reflect the views of USAID or the US Government. Additional funding was provided by the Center for AIDS Research at Emory University (NIH P30 AI050409), and a project grant from the Canadian Institutes for Health Research (PJT-159625 to J.B.J./Z.L.B). Z.L.B. is supported by a Michael Smith Foundation for Health Research (MSFHR) Scholar Award. K.B. was supported with an Action Cycling Atlanta (AV200) Fellowship, and E.H. is a Georgia Research Alliance Eminent Scholar. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                Custom metadata
                vor-update-to-uncorrected-proof
                2020-06-15
                Sequences are available at Genbank under accession numbers MT194125 - MT195535.

                Infectious disease & Microbiology

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