Strong T(H)1-biased CD4 T cell responses are associated with diminished SIV vaccine efficacy

• Type of Material: Article
• Authors: Venkateswarlu Chamcha, Emory University; Pradeep B. J. Reddy, Emory University; Sunil Kannanganat, Emory University; Courtney Wilkins, University of Washington; Sailaja Gangadhara, Emory University; Vijayakumar Velu, Emory University; Richard Green, University of Washington; G. Lynn Law, University of Washington; Jean Chang, University of Washington; James R. Bowen, Emory University; Pamela A. Kozlowski, Louisiana State University; Michelle Lifton, Harvard Medical School; Sampa Santra, Harvard Medical School; Traci Legere, Emory University; Lynette S. Chea, Emory University; Lakshmi Chennareddi, Emory University; Tianwei Yu, Emory University; Mehul Suthar, Emory University; Guido Silvestri, Emory University; Cynthia Derdeyn, Emory University; Michael Gale, University of Washington; Francois Villinger, Emory University; Eric Hunter, Emory University; Rama Amara, Emory University
• Language: English
• Date: 2019-11-20
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 American Association for the Advancement of Science. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.aav1800
• Title of Journal or Parent Work: Science Translational Medicine
• Volume: 11
• Issue: 519
• Keywords: Step; HIV-1 infection; Science & Technology; Protection; Replication; Research & Experimental Medicine; Life Sciences & Biomedicine; Activation; Acquisition; Challenge; Immunity; Medicine, Research & Experimental; Follicular helper-cells; Cell Biology; Simian immunodeficiency virus
• Research Categories: Biology, Bioinformatics; Biology, Biostatistics; Biology, Cell; Health Sciences, Pathology; Health Sciences, Immunology

Abstract

Activated CD4 T cells are a major target of HIV infection. Results from the STEP HIV vaccine trial highlighted a potential role for total activated CD4 T cells in promoting HIV acquisition. However, the influence of vaccine insert-specific CD4 T cell responses on HIV acquisition is not known. Here, using the data obtained from four macaque studies, we show that the DNA prime/modified vaccinia Ankara boost vaccine induced interferon γ (IFNγ+) CD4 T cells [T helper 1 (TH1) cells] rapidly migrate to multiple tissues including colon, cervix, and vaginal mucosa. These mucosal TH1 cells persisted at higher frequencies and expressed higher density of CCR5, a viral coreceptor, compared to cells in blood. After intravaginal or intrarectal simian immunodeficiency virus (SIV)/simian-human immunodeficiency virus (SHIV) challenges, strong vaccine protection was evident only in animals that had lower frequencies of vaccine-specific TH1 cells but not in animals that had higher frequencies of TH1 cells, despite comparable vaccine-induced humoral and CD8 T cell immunity in both groups. An RNA transcriptome signature in blood at 7 days after priming immunization from one study was associated with induction of fewer TH1-type CD4 cells and enhanced protection. These results demonstrate that high and persisting frequencies of HIV vaccine–induced TH1-biased CD4 T cells in the intestinal and genital mucosa can mitigate beneficial effects of protective antibodies and CD8 T cells, highlighting a critical role of priming immunization and vaccine adjuvants in modulating HIV vaccine efficacy.