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Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1).


ABSTRACT: Hepatitis C virus (HCV) persistence is facilitated by exhaustion of CD8+ T cells that express the inhibitory receptor programmed cell death 1 (PD-1). Blockade of PD-1 signaling improves in vitro proliferation of HCV-specific T lymphocytes, but whether antiviral function can be restored in infected individuals is unknown. To address this question, chimpanzees with persistent HCV infection were treated with anti-PD-1 antibodies. A significant reduction in HCV viremia was observed in one of three treated animals without apparent hepatocellular injury. Viremia rebounded in the responder animal when antibody treatment was discontinued. Control of HCV replication was associated with restoration of intrahepatic CD4+ and CD8+ T-cell immunity against multiple HCV proteins. The responder animal had a history of broader T-cell immunity to multiple HCV proteins than the two chimpanzees that did not respond to PD-1 therapy. The results suggest that successful PD-1 blockade likely requires a critical threshold of preexisting virus-specific T cells in liver and warrants consideration of therapeutic vaccination strategies in combination with PD-1 blockade to broaden narrow responses. Anti-PD-1 immunotherapy may also facilitate control of other persistent viruses, notably the hepatitis B virus where options for long-term control of virus replication are limited.

SUBMITTER: Fuller MJ 

PROVIDER: S-EPMC3773803 | biostudies-other | 2013 Sep

REPOSITORIES: biostudies-other

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Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1).

Fuller Michael J MJ   Callendret Benoit B   Zhu Baogong B   Freeman Gordon J GJ   Hasselschwert Dana L DL   Satterfield William W   Sharpe Arlene H AH   Dustin Lynn B LB   Rice Charles M CM   Grakoui Arash A   Ahmed Rafi R   Walker Christopher M CM  

Proceedings of the National Academy of Sciences of the United States of America 20130826 37


Hepatitis C virus (HCV) persistence is facilitated by exhaustion of CD8+ T cells that express the inhibitory receptor programmed cell death 1 (PD-1). Blockade of PD-1 signaling improves in vitro proliferation of HCV-specific T lymphocytes, but whether antiviral function can be restored in infected individuals is unknown. To address this question, chimpanzees with persistent HCV infection were treated with anti-PD-1 antibodies. A significant reduction in HCV viremia was observed in one of three t  ...[more]

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