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

Abstract

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 containedmore » 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.« less

Authors:
 [1];  [1];  [1];  [2];  [3]; ORCiD logo [4];  [5];  [6];  [7];  [7];  [8];  [9];  [1];  [6];  [1];  [10];  [1];  [1]
+ Show Author Affiliations
  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)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE National Nuclear Security Administration (NNSA)
Contributing Org.:
I4C and RV254 Study Groups
OSTI Identifier:
1846143
Report Number(s):
LA-UR-20-25569
Journal ID: ISSN 2352-3964
Grant/Contract Number:  
89233218CNA000001; R21-AI131763; R21-AI138716; UM1-AI126603; U01-AI35041
Resource Type:
Accepted Manuscript
Journal Name:
EBioMedicine
Additional Journal Information:
Journal Volume: 63; Journal ID: ISSN 2352-3964
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; HIV-1; immunotherapy; dendritic cell; cytotoxic T cell; epitopes

Citation Formats

Garcia-Bates, Tatiana M., Palma, Mariana L., Anderko, Renee R., Hsu, Denise C., Ananworanich, Jintanat, Korber, Bette Tina Marie, Gaiha, Gaurav D., Phanuphak, Nittaya, Thomas, Rasmi, Tovanabutra, Sodsai, Walker, Bruce D., Mellors, John W., Piazza, Paolo A., Kroon, Eugene, Riddler, Sharon A., Michael, Nelson L., Rinaldo, Charles R., and Mailliard, Robbie B. Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes. United States: N. p., 2021. Web. doi:10.1016/j.ebiom.2020.103175.
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Garcia-Bates, Tatiana M., Palma, Mariana L., Anderko, Renee R., Hsu, Denise C., Ananworanich, Jintanat, Korber, Bette Tina Marie, Gaiha, Gaurav D., Phanuphak, Nittaya, Thomas, Rasmi, Tovanabutra, Sodsai, Walker, Bruce D., Mellors, John W., Piazza, Paolo A., Kroon, Eugene, Riddler, Sharon A., Michael, Nelson L., Rinaldo, Charles R., & Mailliard, Robbie B. Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes. United States. https://doi.org/10.1016/j.ebiom.2020.103175
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Garcia-Bates, Tatiana M., Palma, Mariana L., Anderko, Renee R., Hsu, Denise C., Ananworanich, Jintanat, Korber, Bette Tina Marie, Gaiha, Gaurav D., Phanuphak, Nittaya, Thomas, Rasmi, Tovanabutra, Sodsai, Walker, Bruce D., Mellors, John W., Piazza, Paolo A., Kroon, Eugene, Riddler, Sharon A., Michael, Nelson L., Rinaldo, Charles R., and Mailliard, Robbie B. Tue . "Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes". United States. https://doi.org/10.1016/j.ebiom.2020.103175. https://www.osti.gov/servlets/purl/1846143.
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@article{osti_1846143,
title = {Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes},
author = {Garcia-Bates, Tatiana M. and Palma, Mariana L. and Anderko, Renee R. and Hsu, Denise C. and Ananworanich, Jintanat and Korber, Bette Tina Marie and Gaiha, Gaurav D. and Phanuphak, Nittaya and Thomas, Rasmi and Tovanabutra, Sodsai and Walker, Bruce D. and Mellors, John W. and Piazza, Paolo A. and Kroon, Eugene and Riddler, Sharon A. and Michael, Nelson L. and Rinaldo, Charles R. and Mailliard, Robbie B.},
abstractNote = {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.},
doi = {10.1016/j.ebiom.2020.103175},
journal = {EBioMedicine},
number = ,
volume = 63,
place = {United States},
year = {Tue Jan 12 00:00:00 EST 2021},
month = {Tue Jan 12 00:00:00 EST 2021}
}
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