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Enhancing SIV-specific immunity in vivo by PD-1 blockade


Chronic immunodeficiency virus infections are characterized by dysfunctional cellular and humoral antiviral immune responses1,2,3. 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 blockade of the co-inhibitory receptor programmed death 1 (PD-1)4,5 during chronic simian immunodeficiency virus (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. Blockade was effective during the early (week 10) as well as late (week 90) 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 control of human immunodeficiency virus infections.

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Figure 1: In vivo PD-1 blockade during chronic SIV infection increases the Gag-CM9-specific CD8 T cells with improved functional quality in both blood and gut.
Figure 2: In vivo PD-1 blockade during chronic SIV infection increases the polyfunctional virus-specific CD8 T cells.
Figure 3: In vivo PD-1 blockade during chronic SIV infection enhances SIV-specific humoral immunity.
Figure 4: In vivo PD-1 blockade reduces plasma viraemia and prolongs survival of SIV-infected macaques.

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Data deposits

Sequencing data related to the Tat SL8/TL8 epitope region have been deposited in GenBank (accession numbers FJ268664FJ268704).


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The authors thank J. D. Altman for provision of Gag CM9 and Tat SL8 tetramers, H. Drake-Perrow for administrative support, and D. Watkins and Wisconsin National Primate Research Center Genotyping Service for Mamu typing of animals. The authors also thank the Yerkes Division of Research Resources for pathology support, Emory CFAR virology core for viral load assays and the NIH AIDS Research and Reference Reagent Program for the provision of peptides. This work was supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases grants R01 AI057029, R01 AI071852, R01 AI074417 to R.R.A.; the Foundation for the NIH through the Grand Challenges in Global Health initiative P51 RR00165 to R.A., G.J.F. and R.R.A.; Yerkes National Primate Research Center base grant P51 RR00165; Emory CFAR grant P30 AI050409; and R24 RR16038 to David I. Watkins.

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.H.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 antibody, 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.

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Correspondence to Rama Rao Amara.

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G.J.F. has patents and receives patent royalties on the PD-1 pathway, and R.A. has patents on the PD-1 pathway.

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Velu, V., Titanji, K., Zhu, B. et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458, 206–210 (2009).

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