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Preservation of Lymphopoietic Potential and Virus Suppressive Capacity by CD8 + T Cells in HIV-2−Infected Controllers

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Preservation of Lymphopoietic Potential and Virus Suppressive Capacity by CD8 + T Cells in HIV-2−Infected Controllers Preservation of Lymphopoietic Potential and Virus Suppressive Capacity by CD8 + T Cells in HIV-2−Infected Controllers This information is current as Mathieu Angin, Glenn Wong, Laura Papagno, Pierre of September 29, 2021. Versmisse, Annie David, Charles Bayard, Bénédicte Charmeteau-De Muylder, Amel Besseghir, Rodolphe Thiébaut, Faroudy Boufassa, Gianfranco Pancino, Delphine Sauce, Olivier Lambotte, Françoise Brun-Vézinet, Sophie Matheron, Sarah L. Rowland-Jones, Rémi Cheynier, Asier Sáez-Cirión, Victor Appay and for the ANRS CO5 Downloaded from IMMUNOVIR-2 Study Group J Immunol 2016; 197:2787-2795; Prepublished online 26 August 2016; doi: 10.4049/jimmunol.1600693 http://www.jimmunol.org/content/197/7/2787 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2016/08/24/jimmunol.160069 Material 3.DCSupplemental References This article cites 66 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/197/7/2787.full#ref-list-1 by guest on September 29, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Preservation of Lymphopoietic Potential and Virus Suppressive Capacity by CD8+ T Cells in HIV-2–Infected Controllers Mathieu Angin,*,1 Glenn Wong,†,‡,1 Laura Papagno,† Pierre Versmisse,* Annie David,* Charles Bayard,† Be´ne´dicte Charmeteau-De Muylder,x,{ Amel Besseghir,‖ Rodolphe Thie´baut,‖ Faroudy Boufassa,# Gianfranco Pancino,* Delphine Sauce,† Olivier Lambotte,**,††,‡‡ Franc¸oise Brun-Ve´zinet,xx Sophie Matheron,{{,‖‖ Sarah L. Rowland-Jones,‡ Re´mi Cheynier,x,{ Asier Sa´ez-Cirio´n,*,1 and Victor Appay,†,1 for the ANRS CO5 IMMUNOVIR-2 Study Group2 Compared with HIV-1, HIV-2 infection is characterized by a larger proportion of slow or nonprogressors. A better understanding of HIV-2 pathogenesis should open new therapeutic avenues to establish control of HIV-1 replication in infected patients. In this study, we Downloaded from studied the production of CD8+ T cells and their capacity for viral control in HIV-2 controllers from the French ANRS CO5 HIV-2 cohort. HIV-2 controllers display a robust capacity to support long-term renewal of the CD8+ T cell compartment by preserving immune resources, including hematopoietic progenitors and thymic activity, which could contribute to the long-term maintenance of the CD8+ T cell response and the avoidance of premature immune aging. Our data support the presence of HIV-2 Gag–specific CD8+ T cells that display an early memory differentiation phenotype and robust effector potential in HIV-2 controllers. Accordingly, to our knowl- edge,weshowforthefirsttimethatHIV-2controllerspossessCD8+ T cells that show an unusually strong capacity to suppress HIV-2 http://www.jimmunol.org/ infection in autologous CD4+ T cells ex vivo, an ability that likely depends on the preservation of host immune resources. This effective and durable antiviral response probably participates in a virtuous circle, during which controlled viral replication permits the pres- ervation of potent immune functions, thus preventing HIV-2 disease progression. The Journal of Immunology, 2016, 197: 2787–2795. n the absence of an effective vaccine that prevents the HIV-1 therapeutic approaches that would modulate the immune system acquisition, the long-term suppression of viral replication in to mimic the immune parameters of HIV-1 controllers, ultimately I infected individuals remains a major objective to prevent leading to a functional cure of HIV-1 infection. further disease progression and dissemination. Although pro- Although HIV-2 shares the same modes of transmission and by guest on September 29, 2021 gression to AIDS can now be significantly delayed by effective intracellular mechanisms of replication as HIV-1, it provides a combinatorial antiretroviral therapy (cART), HIV remission, which unique model of attenuated infection by a HIV. Compared with is observed in HIV-1 controllers (HIC1) (1) and rare patients who HIV-1 infection, HIV-2 infection is predominantly characterized by gain independence from ART after early initiation (2), remains a a slower decline of CD4+ T cells and lower levels of immune priority. Much effort, therefore, has been given to the identifica- activation (1–3). Although HIV-2–infected patients who progress tion of immune correlates of natural HIV control in an attempt to toward disease present similar clinical manifestations and AIDS decipher the immunological mechanisms that underlie effective severity as those infected with HIV-1, they remain a minority control of HIV-1 replication in the absence of ART. A better [∼15–20% of those infected (4)]. Many HIV-2–infected individ- understanding of these correlates would provide insights into uals spontaneously control their infection and remain asymptomatic *Institut Pasteur, Unite´ HIV Inflammation et Persistance, Paris 75015, France; ORCIDs: 0000-0002-6867-4680 (M.A.); 0000-0001-8084-2125 (L.P.); 0000-0001- †Sorbonne Universite´s, Universite´ Pierre et Marie Curie, Universite´ Paris 06, 9666-6808 (A.B.); 0000-0002-3650-6105 (F.B.); 0000-0002-9862-983X (G.P.); DHU FAST, CR7, Centre d’Immunologie et des Maladies Infectieuses, INSERM 0000-0001-7879-6553 (S.M.); 0000-0001-5788-6998 (S.L.R.-J.); 0000-0003-1146- U1135, Paris 75005, France; ‡Nuffield Department of Medicine, Headington, Ox- 660X (R.C.). ford OX3 7FZ, United Kingdom; xINSERM U1016, Institut Cochin, Cytokines and { Received for publication April 19, 2016. Accepted for publication July 23, 2016. Viral Infections Team, Paris 75014, France; CNRS UMR 8104, Universite´ Paris Descartes, Sorbonne Paris Cite´, Paris 75014, France; ‖Centre de Me´thodologie et This work was supported by the Agence Nationale de Recherches sur le SIDA. de Gestion des Essais Cliniques de l’INSERM U1219, Virus de l’Immunode´fi- M.A. received postdoctoral funding from the Agence Nationale de Recherches sur le cience Humaine, He´patites Virales et Comorbidite´s, E´ pide´miologie Clinique et SIDA. Sante´ Publique, Bordeaux 33076, France; #INSERM U1018, Centre de Recherche Address correspondence and reprint requests to Dr. Victor Appay or Dr. Asier Sa´ez- en Epide´miologie et Sante´ des Populations, Universite´ Paris Sud, Le Kremlin Cirio´n, INSERM UMRS 1135, CIMI-Paris, Hoˆpital Pitie´-Salpeˆtrie`re, 75013 Paris, Biceˆtre 94270, France; **INSERM UMR 1184, Immunologie des Maladies Virales France (V.A.) or Unite´ HIV Inflammation et Persistance, Institut Pasteur, 28 rue du et Autoimmunes, Le Kremlin Biceˆtre 94270, France; ††Assistance Publique–Hoˆpitaux Docteur Roux, Paris Cedex 15 75724, France (A.S.-C.). E-mail addresses: victor. de Paris, Service de Me´decine Interne, Hoˆpitaux Universitaires, Le Kremlin Biceˆtre xx [email protected] (V.A.) or [email protected] (A.S.-C.) 94270, France; ‡‡Universite´ Paris Sud, Le Kremlin Biceˆtre 94270, France; Assistance Publique–Hoˆpitaux de Paris, Laboratoire de Virologie, Hoˆpital Bichat, Paris 75018, The online version of this article contains supplemental material. France; {{INSERM UMR 1137, Infections, Antimicrobiens, Mode´lisation, Evolution, ‖‖ Abbreviations used in this article: cART, combination antiretroviral therapy; HIC1/2, Universite´ Paris Diderot, Sorbonne Paris Cite´, Paris 75018, France; and Assistance HIV-1/2 controller; HPC, hematopoietic progenitor cell; IQR, interquartile range; Publique–Hoˆpitaux de Paris, Service des Maladies Infectieuses et Tropicales, Hoˆpital sjTREC, signal joint T cell receptor excision circle; TRIM5a, tripartite interaction Bichat, Paris 75018, France motif 5a. 1M.A., G.W., A.S.-C., and V.A. contributed equally to this work. Ó 2All authors in the ANRS CO5 IMMUNOVIR-2 Study Group appear at the end of Copyright 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 this article. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600693 2788 EFFECTIVE CD8+ T CELLS IN HIV-2–INFECTED CONTROLLERS while maintaining undetectable viral loads, signifying a high All participants gave their written informed consent. The study was prevalence of HIV-2 controllers (HIC2) [9.1% of HIC2 in the approved by the institutional ethics committee (i.e., Comite´ de Protection ANRS CO5 HIV-2 cohort (5) versus 0.22% HIC1 in the ANRS des Personnes of Ile de France XI). CO4 French Hospital Database on HIV (6)]. Deciphering the Flow cytometry and reagents immune correlates of HIV-2 control and contrasting these findings To generate tetramers, immunodominant HIV-2 epitopes were identified by with those from HIV-1 controllers may illuminate the key features screening HIV-2 p27 overlapping peptides in IFN-g ELISPOT assays using of HIV pathogenesis and provide critical information on what is HLA-typed HIV-2–infected patient PBMC, going on to define the optimal needed to establish natural control of HIV. epitope sequences and length (15). HLA-B*5301 p27 TPYDINQML It is well established that CD8+ T cell–mediated immunity is (TL9) and p27 DRFYKSLRA (DA9) tetramers were synthesized as de- critical in the control of HIV-1 replication from the earliest days of scribed previously (17). PBMC were stained with pretitrated concentra- tions of pentamer/tetramer (conjugated to PE), followed by a panel of Abs acute HIV-1 infection. However, the HIV-specific T cell response as described previously (18). Directly conjugated and unconjugated Abs declines over time and is often lost in the later phases of chronic were obtained from the following vendors: BD Biosciences: CD34 (PE), infection (7).
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