Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes
Tatiana M. Garcia-Bates,
Mariana L. Palma,
Renee R. Anderko,
Denise C. Hsu,
Jintanat Ananworanich,
Bette T. Korber,
Gaurav D. Gaiha,
Nittaya Phanuphak,
Rasmi Thomas,
Sodsai Tovanabutra,
Bruce D. Walker,
John W. Mellors,
Paolo A. Piazza,
Eugene Kroon,
Sharon A. Riddler,
Nelson L. Michael,
Charles R. Rinaldo,
Robbie B. Mailliard
Affiliations
Tatiana M. Garcia-Bates
Department of Infectious Diseases and Microbiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, United States
Mariana L. Palma
Department of Infectious Diseases and Microbiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, United States
Renee R. Anderko
Department of Infectious Diseases and Microbiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, United States
Denise C. Hsu
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
Jintanat Ananworanich
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
Bette T. Korber
Los Alamos National Laboratory, Los Alamos, NM, New Mexico Consortium, Los Alamos, NM, United States
Gaurav D. Gaiha
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, United States; Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, United States
Nittaya Phanuphak
SEARCH, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand
Rasmi Thomas
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
Sodsai Tovanabutra
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
Bruce D. Walker
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
John W. Mellors
Institute for Medical Engineering and Science, MIT, Cambridge, MA, United States
Paolo A. Piazza
Department of Infectious Diseases and Microbiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, United States
Eugene Kroon
SEARCH, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand
Sharon A. Riddler
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
Nelson L. Michael
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
Charles R. Rinaldo
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
Robbie B. Mailliard
Department of Infectious Diseases and Microbiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, United States; Corresponding author.
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.
