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      Enhancing SIV-Specific Immunity In Vivo by PD-1 Blockade

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          Abstract

          Chronic immunodeficiency virus infections are characterized by dysfunctional cellular and humoral antiviral immune responses. As such, immune modulatory therapies that enhance and/or restore the function of virus-specific immunity may protect from disease progression. Here, we investigate the safety and immune restoration potential of the blockade of co-inhibitory receptor programmed death-1 (PD-1) during chronic SIV infection in macaques. We demonstrate that PD-1 blockade using an antibody to PD-1 is well tolerated and results in rapid expansion of virus-specific CD8 T cells with improved functional quality. This enhanced T cell immunity was seen in the blood and also in the gut, a major reservoir of SIV infection. PD-1 blockade also resulted in proliferation of memory B cells and increases in SIV envelope-specific antibody. These improved immune responses were associated with significant reductions in plasma viral load and also prolonged the survival of SIV-infected macaques. Impressively, blockade was effective during the early (wk10) as well as late (∼wk90) phases of chronic infection even under conditions of severe lymphopenia. These results demonstrate enhancement of both cellular and humoral immune responses during a pathogenic immunodeficiency virus infection by blocking a single inhibitory pathway and identify a novel therapeutic approach for HIV/AIDS.

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          Most cited references 17

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          Immunology of hepatitis B virus and hepatitis C virus infection.

          More than 500 million people worldwide are persistently infected with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV) and are at risk of developing chronic liver disease, cirrhosis and hepatocellular carcinoma. Despite many common features in the pathogenesis of HBV- and HCV-related liver disease, these viruses markedly differ in their virological properties and in their immune escape and survival strategies. This review assesses recent advances in our understanding of viral hepatitis, contrasts mechanisms of virus-host interaction in acute hepatitis B and hepatitis C, and outlines areas for future studies.
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            Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies.

            CT-011 is a humanized IgG1 monoclonal antibody that modulates the immune response through interaction with PD-1, a protein belonging to the B7 receptor family present on lymphocytes. The objectives of this phase I study were to assess the dose-limiting toxicities, to determine the maximum tolerated dose, and to study the pharmacokinetics of CT-011 administered once to patients with advanced hematologic malignancies. Seventeen patients were treated with escalating doses of CT-011 ranging from 0.2 to 6 mg/kg. For pharmacokinetic analysis, blood samples were withdrawn from the patients before and immediately after treatment and at 24 hours, 48 hours, and on days 7, 14, and 21. CT-011 blood levels were assessed with a specific ELISA and derived concentrations were used to calculate pharmacokinetic parameters. Activation of the immune system was assessed by measuring peripheral blood CD4+, CD8+, and CD69+ lymphocytes. The study showed the antibody to be safe and well tolerated in this patient population. No single maximum tolerated dose was defined in this study. Clinical benefit was observed in 33% of the patients with one complete remission. Pharmacokinetic analyses show that serum Cmax and the AUC of CT-011 increased proportionally with dose. The median t1/2 of CT-011 ranged from 217 to 410 hours. Sustained elevation in the percentage of peripheral blood CD4+ lymphocytes was observed up to 21 days following CT-011 treatment. A single administration of 0.2 to 6.0 mg/kg of CT-011 is safe and well tolerated in patients with advanced hematologic malignancies.
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              T cells and viral persistence: lessons from diverse infections.

              Persistent virus infections create specific problems for their hosts. Although the dynamics of immune responses after acute infection are well studied and very consistent, especially in mouse models, the patterns of responses noted during persistent infection are more complex and differ depending on the infection. In particular, CD8(+) T cell responses differ widely in quantity and quality. In this review we examine these diverse responses and ask how they may arise; in particular, we discuss the function of antigen re-encounter and the CD4(+) T cell responses to and the escape strategies of specific viruses. We focus on studies of four main human pathogens, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus and hepatitis C virus, and their animal models.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                17 March 2009
                10 December 2008
                12 March 2009
                28 September 2009
                : 458
                : 7235
                : 206-210
                Affiliations
                [1 ]Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA
                [2 ]Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA, 30329, USA
                [3 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
                [4 ]Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
                [5 ]University of Pennsylvania School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
                Author notes
                [*]

                These authors contributed equally to this work.

                [†]

                Corresponding Author: 954 Gatewood Road, Atlanta, GA 30329; Phone: 404-727-8765; Fax: 407-727-7768; E-mail: ramara@ 123456emory.edu

                Author Contributions

                V.V and K.T. contributed to the design of experiments, conducted analyses on T cell responses, and contributed to manuscript preparation; S. H. performed analyses on T cell phenotyping. T.V. performed analyses on viral escape. L. L and A.P. performed analyses on humoral responses; L.C. performed the statistical analysis; G.S. supervised the analyses on viral escape and contributed to manuscript preparation; B. Z and G.J.F. developed and provided the anti-human PD-1 blocking Ab, and contributed to the design of experiments and manuscript preparation. R.A. contributed to the concept, design of experiments and manuscript preparation. R.R.A. supervised the entire project, designed and coordinated the experiments, and contributed to manuscript preparation.

                Sequencing data related to Tat SL8/TL8 epitope region have been deposited in GenBank (accession #s FJ268664-FJ268704)

                Article
                nihpa103054
                10.1038/nature07662
                2753387
                19078956
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI074417-02 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI074417-01A1 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI057029-05 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI057029-04 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI057029-03 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI057029-02 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI057029-01 ||AI
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