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Author Notes:

Dr. Rama Amara. Phone: (404) 727-8765; FAX: (404) 727-7768. Email: ramara@emory.edu

S.A.R. and B.Y. designed research, performed research, analyzed and interpreted the data, and wrote the manuscript. A.P.B. and K.N.M. designed research, performed research. S.W. performed qPCR analyses of SIV RNA and DNA in monkey samples. T.H.V. supervised the qPCR analyses of SIV RNA and DNA in monkey samples. G.J.F. synthesized primatized PD-1 mAb and provided helpful discussions regarding the study design. R.R.A. conceived the study. R.A. and R.R.A. designed the research and interpreted data throughout the study. R.R.A. supervised the research and wrote the manuscript.

We thank S. Ehnert, J. Sherrie, and all the veterinary staff at Yerkes for animal care; L. Shan and CFAR virology core for viral RNA and CA SIV DNA analysis; and K. Gill, B. Cervasi, and CFAR immunology core for help with flow cytometry. The SIVmac239 strain used to infect the RMs was provided by G. Silvestri at Emory University School of Medicine, and anti-Gag tetramers were provided by NIH Tetramer Core Facility at Emory. We thank R. Wang and K. Reimann at the University of Massachusetts Medical School for the RM constant regions of the IgG4 used in EH12 (anti-PD-1) mAb. We thank V. Velu for constructive discussion.

R.A., G.J.F., and R.R.A. are co-inventors of PD-1 technology that has been licensed to Genentech by Emory University. G.J.F. has patents/pending royalties on the PD-1/PD-L1 pathway from Roche, Merck MSD, Bristol-Myers-Squibb, Merck KGA, Boehringer-Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic, and Novartis. G.J.F. has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, Origimed, Triursus, iTeos, NextPoint, IgM, Jubilant, and GV20. G.J.F. has equity in Nextpoint, Triursus, Xios, iTeos, IgM, and GV20. The other authors declare that they have no competing interests.


Research Funding:

This work was supported by the NIH R37AI112787 to R.R.A., P01AI056299 to G.J.F., NCRR/NIH base grant P51 OD011132 to Yerkes National Primate Research Center; and Emory CFAR grant P30 AI050409.

S.A.R. and B.Y. are the recipients of AIDS Vaccine 200 fellowship award.

This research project was supported in part by the Emory University Integrated Cellular Imaging Microscopy Core.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • CD4(+)
  • HIV-1

PD-1 blockade and vaccination provide therapeutic benefit against SIV by inducing broad and functional CD8(+) T cells in lymphoid tissue


Journal Title:



Volume 6, Number 63


, Pages eabh3034-eabh3034

Type of Work:

Article | Post-print: After Peer Review


During antiretroviral therapy (ART), most of the human immunodeficiency virus (HIV) reservoirs persist in the B cell follicles (BCFs) of lymphoid tissue. Thus, for HIV cure strategies, it is critical to generate cytolytic CD8+ T cells that home to BCF, reduce the reservoir burden, and maintain strong antiviral responses in the absence of ART. Here, using a chronic simian immunodeficiency virus (SIV)/rhesus macaque model, we showed that therapeutic vaccination under ART using a CD40L plus TLR7 agonist-adjuvanted DNA/modified vaccinia Ankara vaccine regimen induced robust and highly functional, SIV-specific CD4+ and CD8+ T cell responses. In addition, the vaccination induced SIV-specific CD8+ T cells in the lymph nodes (LNs) that could home to BCF. Administration of PD-1 blockade before initiation of ART and during vaccination markedly increased the frequency of granzyme B+ perforin+ CD8+ T cells in the blood and LN, enhanced their localization in germinal centers of BCF, and reduced the viral reservoir. After ART interruption, the vaccine + anti-PD-1 antibody-treated animals, compared with the vaccine alone and ART alone control animals, displayed preservation of the granzyme B+ CD8+ T cells in the T cell zone and BCF of LN, maintained high SIV antigen-recognition breadth, showed control of reemerging viremia, and improved survival. Our findings revealed that PD-1 blockade enhanced the therapeutic benefits of SIV vaccination by improving and sustaining the function and localization of vaccine-induced CD8+ T cells to BCF and decreasing viral reservoirs in lymphoid tissue. This work has potential implications for the development of curative HIV strategies.
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