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

Journal Article · Tue Jan 12 00:00:00 EST 2021 · EBioMedicine

DOI:https://doi.org/10.1016/j.ebiom.2020.103175· OSTI ID:1846143

Garcia-Bates, Tatiana M. ^[1]; Palma, Mariana L. ^[1]; Anderko, Renee R. ^[1]; Hsu, Denise C. ^[2]; Ananworanich, Jintanat ^[3]; Korber, Bette Tina Marie ^[4]; Gaiha, Gaurav D. ^[5]; Phanuphak, Nittaya ^[6]; Thomas, Rasmi ^[7]; Tovanabutra, Sodsai ^[7]; Walker, Bruce D. ^[8]; Mellors, John W. ^[9]; Piazza, Paolo A. ^[1]; Kroon, Eugene ^[6]; Riddler, Sharon A. ^[1]; Michael, Nelson L. ^[10]; Rinaldo, Charles R. ^[1]; Mailliard, Robbie B. ^[1]

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1. Univ. of Pittsburgh, PA (United States)
2. Armed Forces Research Institute of Medical Sciences, Bangkok (Thailand); 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); Thai Red Cross AIDS Research Centre, Bangkok (Thailand)
3. 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); Thai Red Cross AIDS Research Centre, Bangkok (Thailand); Univ. of Amsterdam (Netherlands)
4. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
5. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA (United States); Massachusetts General Hospital, Boston, MA (United States)
6. Thai Red Cross AIDS Research Centre, Bangkok (Thailand)
7. 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)
8. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA (United States); Massachusetts General Hospital, Boston, MA (United States); Broad Institute of MIT and Harvard, Cambridge, MA (United States); Howard Hughes Medical Institute, Chevy Chase, MD (United States)
9. Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
10. Walter Reed Army Institute of Research Silver Spring, MD (United States)

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). 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. 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. 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.

• Research Organization: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
• Sponsoring Organization: National Institutes of Health (NIH); USDOE National Nuclear Security Administration (NNSA)
• Contributing Organization: I4C and RV254 Study Groups
• Grant/Contract Number: 89233218CNA000001
• OSTI ID: 1846143
• Report Number(s): LA-UR-20-25569
• Journal Information: EBioMedicine, Journal Name: EBioMedicine Vol. 63; ISSN 2352-3964
• Publisher: Elsevier
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
HIV-1
cytotoxic T cell
dendritic cell
epitopes
immunotherapy