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

• Published in: Science immunology Vol. 6; no. 63; p. eabh3034
• Main Authors: Rahman, Sheikh Abdul, Yagnik, Bhrugu, Bally, Alexander P, Morrow, Kristen N, Wang, Shelly, Vanderford, Thomas H, Freeman, Gordon J, Ahmed, Rafi, Amara, Rama Rao
• Format: Journal Article
• Language: English
• Published: United States 10.09.2021
• Subjects: CD8-Positive T-Lymphocytes - immunology; Humans; Lymphoid Tissue - immunology; Programmed Cell Death 1 Receptor - immunology; Simian Immunodeficiency Virus - immunology; Vaccination; Viral Vaccines - immunology
• ISSN: 2470-9468
• DOI: 10.1126/sciimmunol.abh3034

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.