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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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 17 March 2009

Publication date (Electronic): 10 December 2008

Publication date (Print): 12 March 2009

Publication date PMC-release: 28 September 2009

Volume: 458

Issue: 7235

Pages: 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

Manuscript ID: nihpa103054

DOI: 10.1038/nature07662

PMC ID: 2753387

PubMed ID: 19078956

SO-VID: 9201ba86-c425-46c0-b963-1dae0fecc69e