Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes.

Autor:	Garcia-Bates TM; Department of Infectious Diseases and Microbiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, United States., Palma ML; Department of Infectious Diseases and Microbiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, United States., Anderko RR; Department of Infectious Diseases and Microbiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, United States., Hsu DC; Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States; Center for Infectious Diseases Research, Walter Reed Army Institute of Research Silver Spring, MD, United States; SEARCH, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand., Ananworanich J; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States; Center for Infectious Diseases Research, Walter Reed Army Institute of Research Silver Spring, MD, United States; SEARCH, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand; Department of Global Health, Amsterdam University Medical Centers, University of Amsterdam, and Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands., Korber BT; Los Alamos National Laboratory, Los Alamos, NM, New Mexico Consortium, Los Alamos, NM, United States., Gaiha GD; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, United States; Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, United States., Phanuphak N; SEARCH, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand., Thomas R; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States; Center for Infectious Diseases Research, Walter Reed Army Institute of Research Silver Spring, MD, United States., Tovanabutra S; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States; Center for Infectious Diseases Research, Walter Reed Army Institute of Research Silver Spring, MD, United States., Walker BD; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, United States; Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, United States; The Broad Institute of MIT and Harvard, Cambridge, MA, United States; Howard Hughes Medical Institute, Chevy Chase, MD, United States., Mellors JW; Institute for Medical Engineering and Science, MIT, Cambridge, MA, United States., Piazza PA; Department of Infectious Diseases and Microbiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, United States., Kroon E; SEARCH, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand., Riddler SA; Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Michael NL; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States; Center for Infectious Diseases Research, Walter Reed Army Institute of Research Silver Spring, MD, United States., Rinaldo CR; Department of Infectious Diseases and Microbiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, United States; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States., Mailliard RB; Department of Infectious Diseases and Microbiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, United States. Electronic address: rbm19@pitt.edu.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2021 Jan; Vol. 63, pp. 103175. Date of Electronic Publication: 2021 Jan 12.
DOI:	10.1016/j.ebiom.2020.103175
Abstrakt:	Background: During early HIV-1 infection, immunodominant T cell responses to highly variable epitopes lead to the establishment of immune escape virus variants. Here we assessed a type 1-polarized monocyte-derived dendritic cell (MDC1)-based approach to selectively elicit cytotoxic T lymphocyte (CTL) responses against highly conserved and topologically important HIV-1 epitopes in HIV-1-infected individuals from the Thailand RV254/SEARCH 010 cohort who initiated antiretroviral therapy (ART) during early infection (Fiebig stages I-IV). Methods: Autologous MDC1 were used as antigen presenting cells to induce in vitro CTL responses against HIV-1 Gag, Pol, Env, and Nef as determined by flow cytometry and ELISpot assay. Ultra-conserved or topologically important antigens were respectively identified using the Epigraph tool and a structure-based network analysis approach and compared to overlapping peptides spanning the Gag proteome. Findings: MDC1 presenting either the overlapping Gag, Epigraph, or Network 14-21mer peptide pools consistently activated and expanded HIV-1-specific T cells to epitopes identified at the 9-13mer peptide level. Interestingly, some CTL responses occurred outside known or expected HLA associations, providing evidence of new HLA-associated CTL epitopes. Comparative analyses demonstrated more sequence conservation among Epigraph antigens but a higher magnitude of CTL responses to Network and Gag peptide groups. Importantly, CTL responses against topologically constrained Gag epitopes contained in both the Network and Gag peptide pools were selectively enhanced in the Network pool-initiated cultures. Interpretation: Our study supports the use of MDC1 as a therapeutic strategy to induce and focus CTL responses toward putative fitness-constrained regions of HIV-1 to prevent immune escape and control HIV-1 infection. Funding: A full list of the funding sources is detailed in the Acknowledgment section of the manuscript. Competing Interests: Declaration of Competing Interests JWM reports grants from the NIH and Gilead Sciences, personal fees (consultant) from Gilead Sciences, Merck, Accelevir Diagnostics, and others from Co-Crystal Pharmaceuticals, Inc., Infectious Diseases Connect, and Abound Bio, Inc., outside the submitted work; JA reports grants from The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the U.S. Department of Defense, and others from ViiV Healthcare, Gilead, Merck, Roche, and AbbVie, outside the submitted work; SAR reports grants from the NIH; RBM and CRR report a patent PCT/US2020/039843, Pitt Ref: 04973 (pending) for use of antigen presenting cells in HIV therapy: GDG reports a patent PCT/US2020/022403 (pending), Network Immunogen Composition; and BTK reports several provisional patents not directly related to the present work but to HIV vaccines in general. The most recent of these patents is US 2020/0055901, Signature-based human immunodeficiency virus envelope trimer vaccines and methods of using the same. (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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