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      Immunological biomarkers predict HIV-1 viral rebound after treatment interruption

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          Abstract

          Treatment of HIV-1 infection with antiretroviral therapy (ART) in the weeks following transmission may induce a state of ‘post-treatment control' (PTC) in some patients, in whom viraemia remains undetectable when ART is stopped. Explaining PTC could help our understanding of the processes that maintain viral persistence. Here we show that immunological biomarkers can predict time to viral rebound after stopping ART by analysing data from a randomized study of primary HIV-1 infection incorporating a treatment interruption (TI) after 48 weeks of ART (the SPARTAC trial). T-cell exhaustion markers PD-1, Tim-3 and Lag-3 measured prior to ART strongly predict time to the return of viraemia. These data indicate that T-cell exhaustion markers may identify those latently infected cells with a higher proclivity to viral transcription. Our results may open new avenues for understanding the mechanisms underlying PTC, and eventually HIV-1 eradication.

          Abstract

          In some HIV-1-infected individuals, viraemia remains undetectable after antiretroviral treatment, but which of these patients will experience viral rebound is difficult to predict. Here the authors show that T cell exhaustion markers before treatment are predictive of shorter time to viral rebound.

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          Most cited references40

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          Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma

          New England Journal of Medicine, 373(1), 23-34
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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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              Declining Morbidity and Mortality among Patients with Advanced Human Immunodeficiency Virus Infection

              National surveillance data show recent, marked reductions in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). To evaluate these declines, we analyzed data on 1255 patients, each of whom had at least one CD4+ count below 100 cells per cubic millimeter, who were seen at nine clinics specializing in the treatment of human immunodeficiency virus (HIV) infection in eight U.S. cities from January 1994 through June 1997. Mortality among the patients declined from 29.4 per 100 person-years in the first quarter of 1995 to 8.8 per 100 in the second quarter of 1997. There were reductions in mortality regardless of sex, race, age, and risk factors for transmission of HIV. The incidence of any of three major opportunistic infections (Pneumocystis carinii pneumonia, Mycobacterium avium complex disease, and cytomegalovirus retinitis) declined from 21.9 per 100 person-years in 1994 to 3.7 per 100 person-years by mid-1997. In a failure-rate model, increases in the intensity of antiretroviral therapy (classified as none, monotherapy, combination therapy without a protease inhibitor, and combination therapy with a protease inhibitor) were associated with stepwise reductions in morbidity and mortality. Combination antiretroviral therapy was associated with the most benefit; the inclusion of protease inhibitors in such regimens conferred additional benefit. Patients with private insurance were more often prescribed protease inhibitors and had lower mortality rates than those insured by Medicare or Medicaid. The recent declines in morbidity and mortality due to AIDS are attributable to the use of more intensive antiretroviral therapies.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                2041-1723
                09 October 2015
                2015
                : 6
                : 8495
                Affiliations
                [1 ]Nuffield Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, John Radcliffe Hospital , Oxford OX1 3SY, UK
                [2 ]Institute for Emerging Infections, The Oxford Martin School , Oxford OX1 3BD, UK
                [3 ]Division of Medicine, Wright Fleming Institute, Imperial College , London W2 1PG, UK
                [4 ]Caldecot Centre, King's College Hospital NHS Foundation Trust , London SE5 9RS, UK
                [5 ]Oxford National Institute of Health Research Biomedical Research Centre , Oxford OX3 7LE, UK
                [6 ]St Vincent's Centre for Applied Medical Research and The Kirby Institute, UNSW Australia , Sydney, New South Wales 2052, Australia
                [7 ]Department of HIV and Sexual Health, Brighton and Sussex University Hospitals , Brighton BN2 5BE, UK
                [8 ]Division of Infection and Immunity, University College London , London WC1E 6BT, UK
                [9 ]Projeto Praça Onze, Hospital Escola São Francisco de Assis, Universidade Federal do Rio de Janeiro , Rio de Janeiro RJ 21941-901, Brazil
                [10 ]Department of Infectious Diseases, Ospedale San Raffaele , Milan 20132, Italy
                [11 ]MRC Clinical Trials Unit at UCL Institute of Clinical Trials & Methodology , London WC2B 6NH, UK
                Author notes
                Author information
                http://orcid.org/0000-0003-3549-5472
                Article
                ncomms9495
                10.1038/ncomms9495
                4633715
                26449164
                73d6a52a-3161-421b-9285-586ddd36141f
                Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 13 March 2015
                : 27 August 2015
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