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

• Type of Material: Article
• Authors: Sheikh Rahman, Emory University; Bhrugu Yagnik, Emory University; Alexander P Bally, Emory University; Kristen Morrow, Emory University; Shelly Wang, Emory University; Thomas Vanderford, Emory University; Gordon J Freeman, Dana Farber Cancer Institute; Rafi Ahmed, Emory University; Rama Amara, Emory University
• Language: English
• Date: 2021-09-01
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
• Final Published Version (URL): http://dx.doi.org/10.1126/sciimmunol.abh3034
• Title of Journal or Parent Work: SCIENCE IMMUNOLOGY
• Volume: 6
• Issue: 63
• Start Page: eabh3034
• End Page: eabh3034
• Grant/Funding Information: 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.; 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.
• Keywords: PERSISTENCE; STIMULATION; VIRAL RESERVOIR; EXPRESSION; INFECTION; RHESUS MACAQUES; HIV-1; CD4(+); Immunology; Life Sciences & Biomedicine; EXPANSION; Science & Technology; CELLULAR-IMMUNITY

Abstract

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.