title: Peptide Processing Is Critical for T-Cell Memory Inflation and May Be Optimized to Improve Immune Protection by CMV-Based Vaccine Vectors.
abstract: Cytomegalovirus (CMV) elicits long-term T-cell immunity of unparalleled strength, which has allowed the development of highly protective CMV-based vaccine vectors. Counterintuitively, experimental vaccines encoding a single MHC-I restricted epitope offered better immune protection than those expressing entire proteins, including the same epitope. To clarify this conundrum, we generated recombinant murine CMVs (MCMVs) encoding well-characterized MHC-I epitopes at different positions within viral genes and observed strong immune responses and protection against viruses and tumor growth when the epitopes were expressed at the protein C-terminus. We used the M45-encoded conventional epitope HGIRNASFI to dissect this phenomenon at the molecular level. A recombinant MCMV expressing HGIRNASFI on the C-terminus of M45, in contrast to wild-type MCMV, enabled peptide processing by the constitutive proteasome, direct antigen presentation, and an inflation of antigen-specific effector memory cells. Consequently, our results indicate that constitutive proteasome processing of antigenic epitopes in latently infected cells is required for robust inflationary responses. This insight allows utilizing the epitope positioning in the design of CMV-based vectors as a novel strategy for enhancing their efficacy.
authors.affiliation: Department of Vaccinology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Iryna
authors.initials: I
authors.lastname: Dekhtiarenko
authors.affiliation: TomegaVax Inc., Portland, Oregon, United States of America.
authors.forename: Robert B
authors.identifier: http://orcid.org/0000-0001-6290-9322
authors.initials: RB
authors.lastname: Ratts
authors.affiliation: Immunotherapy and prevention, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Molecular Vaccine Design, German Center for Infection Research (DZIF), Heidelberg, Germany.
authors.forename: Renata
authors.initials: R
authors.lastname: Blatnik
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Lian N
authors.initials: LN
authors.lastname: Lee
authors.affiliation: Department of Vaccinology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Department of Vaccinology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Borkner
authors.affiliation: Department of Vaccinology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Oduro
authors.affiliation: Department of Vaccinology, Helmholtz Centre for Infection Research, Braunschweig, Germany.|Dar es Salaam University College of Education, Dar es Salaam, Tanzania.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Marandu
authors.affiliation: Immunotherapy and prevention, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Molecular Vaccine Design, German Center for Infection Research (DZIF), Heidelberg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hoppe
authors.affiliation: Institute for Virology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Ruzsics
authors.affiliation: Department of Vaccinology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Sonnemann
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors.forename: Mandana
authors.identifier: http://orcid.org/0000-0003-1299-0817
authors.initials: M
authors.lastname: Mansouri
authors.affiliation: TomegaVax Inc., Portland, Oregon, United States of America.
authors.forename: Christine
authors.initials: C
authors.lastname: Meyer
authors.affiliation: Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Niels A W
authors.identifier: http://orcid.org/0000-0001-9190-6497
authors.initials: NA
authors.lastname: Lemmermann
authors.affiliation: Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Rafaela
authors.initials: R
authors.lastname: Holtappels
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Ramon
authors.initials: R
authors.lastname: Arens
authors.affiliation: Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Paul
authors.identifier: http://orcid.org/0000-0003-4307-9161
authors.initials: P
authors.lastname: Klenerman
authors.affiliation: TomegaVax Inc., Portland, Oregon, United States of America.|Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
authors.forename: Klaus
authors.initials: K
authors.lastname: Früh
authors.affiliation: Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Reddehase
authors.affiliation: Immunotherapy and prevention, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Molecular Vaccine Design, German Center for Infection Research (DZIF), Heidelberg, Germany.
authors.forename: Angelika B
authors.initials: AB
authors.lastname: Riemer
authors.affiliation: Department of Vaccinology, Helmholtz Centre for Infection Research, Braunschweig, Germany.|German Center for Infection Research (DZIF), Partner site Hannover/Braunschweig, Germany.|Institute for Virology, Medical School Hannover, Germany.
authors.forename: Luka
authors.initials: L
authors.lastname: Cicin-Sain
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002853:Chromatography, Liquid; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005434:Flow Cytometry; D006566:Herpesviridae Infections / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D013058:Mass Spectrometry; D051379:Mice; D018146:Muromegalovirus / Q000276:immunology; D016297:Mutagenesis, Site-Directed; D010455:Peptides; D014614:Vaccines, Synthetic / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D010455:Peptides; D014614:Vaccines, Synthetic; D014764:Viral Proteins; D014765:Viral Vaccines