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      Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study


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          Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.

          Author Summary

          There is a renewed scientific interest in developing strategies allowing long-term remission in HIV-1-infected individuals. Very rare (<1%) patients are able to spontaneously control viremia to undetectable levels (HIV controllers, HICs). However, the possibility to translate their mechanisms of control to other patients is uncertain. Starting antiretroviral therapy during primary infection may provide significant benefits to HIV-infected patients (i.e. reduction of viral reservoirs, preservation of immune responses, protection from chronic immune activation). Indeed, we have observed that some HIV-infected patients interrupting a prolonged antiretroviral therapy initiated close to primary infection are able to control viremia afterwards. We present here 14 of such post-treatment controllers (PTCs). We show that PTCs have achieved control of infection through mechanisms that are, at least in part, different from those commonly observed in HICs and that their capacity to control is likely related to early therapeutic intervention. We found that PTCs were able, after therapy interruption, to keep, and in some cases further reduce, a weak viral reservoir. This might be related to the low contribution of long-lived cells to the HIV-reservoir in these patients. Finally, we estimated the probability of maintaining viral control at 24 months post-early treatment interruption to be ∼15%, which is much higher than the one expected for spontaneous control.

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          Author and article information

          Role: Editor
          PLoS Pathog
          PLoS Pathog
          PLoS Pathogens
          Public Library of Science (San Francisco, USA )
          March 2013
          March 2013
          14 March 2013
          : 9
          : 3
          [1 ]Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France
          [2 ]Université Pierre et Marie Curie, INSERM UMR-S 945 Immunité et Infection, Hôpital Pitié-Salpêtrière, Paris, France
          [3 ]Centre Hospitalier Régional d'Orléans, Service des Maladies Infectieuses et Tropicales, Orléans, France
          [4 ]AP-HP, CHU Necker-Enfants Malades, Laboratoire de Virologie, Paris, France
          [5 ]EA 3620, Université Paris-Descartes, Sorbonne Paris Cité, Paris, France
          [6 ]INSERM U1012, Université Paris-Sud 11, Le Kremlin Bicêtre, France
          [7 ]UPMC Univ Paris 06, UMR_S 943, Paris, France
          [8 ]INSERM, U943, Paris, France
          [9 ]AP-HP, Hôtel-Dieu, Paris, France
          [10 ]INSERM U1018, Université Paris-Sud 11, Le Kremlin Bicêtre, France
          [11 ]AP-HP, Hôpital de Bicêtre, Service de Médecine Interne, Le Kremlin Bicêtre, France
          [12 ]AP-HP, Hôpital de Bicêtre, Département d'épidémiologie, Le Kremlin Bicêtre, France
          [13 ]AP-HP, Groupe hospitalier Pitié-Salpétrière, Service de Maladies Infectieuses et Tropicales, Paris, France
          SAIC-Frederick, United States of America
          Author notes

          ¶ Membership of the ANRS VISCONTI Study Group is provided in Text S1.

          The authors have declared that no competing interests exist.

          Coordinated inclusion of patients: LH JPV FB OL TP LM. Discussed results: ASC CB LH IG VAF CG JPV TP LM DC AV GP BA CR. Conceived and designed the experiments: ASC LH AV GP BA CR. Performed the experiments: ASC CB VAF IG CL VP PV AM BD JG. Analyzed the data: ASC CB VAF IG CL VP JG FB AV DC GP BA CR. Contributed reagents/materials/analysis tools: LH CG JPV FB TP OL CG LM. Wrote the paper: ASC CB.


          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
          Pages: 12
          The VISCONTI study (Viro-Immunological Sustained CONtrol after Treatment Interruption) was funded by the ANRS, the French National Agency for Research on AIDS and Viral Hepatitis (Grant ANRS EP47). CB and BD received predoctoral fellowships from UPMC and ANRS, respectively. CL received a postdoctoral fellowship from ANRS. GP was funded by INSERM. ( http://www.anrs.fr, http://www.inserm.fr, http://www.upmc.fr). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
          Research Article
          Clinical Immunology
          Adaptive Immunity
          Immune Activation
          Immune Defense
          Immunity to Infections
          Immune Response
          Infectious Diseases
          Viral Diseases
          Retrovirology and HIV immunopathogenesis
          Infectious Disease Control

          Infectious disease & Microbiology
          Infectious disease & Microbiology


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