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Modulation of MHC-E transport by viral decoy ligands is required for RhCMV/SIV vaccine efficacy

Marieke Verweij, Scott G. Hansen, Ravi Iyer, Nessy John, Daniel Malouli, David Morrow, Isabel Scholz, Jennie Womack, Shaheed Abdulhaqq, Roxanne M. Gilbride, Colette M. Hughes, Abigail B. Ventura, Julia C. Ford, Andrea N. Selseth, Kelli Oswald, Rebecca Shoemaker, Brian Berkemeier, William J. Bosche, Michael Hull, Jason Shao, Jonah B. Sacha, Michael K. Axthelm, Paul T. Edlefsen, Jeffrey D. Lifson, Louis J. Picker, View ORCID ProfileKlaus Früh
doi: https://doi.org/10.1101/2020.09.30.321158
Marieke Verweij
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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Scott G. Hansen
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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Ravi Iyer
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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Nessy John
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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Daniel Malouli
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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David Morrow
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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Isabel Scholz
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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Jennie Womack
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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Shaheed Abdulhaqq
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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Roxanne M. Gilbride
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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Colette M. Hughes
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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Abigail B. Ventura
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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Julia C. Ford
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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Andrea N. Selseth
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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Kelli Oswald
2AIDS and Cancer Virus Program, Frederick National Laboratory, Frederick, MD 21702
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Rebecca Shoemaker
2AIDS and Cancer Virus Program, Frederick National Laboratory, Frederick, MD 21702
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Brian Berkemeier
2AIDS and Cancer Virus Program, Frederick National Laboratory, Frederick, MD 21702
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William J. Bosche
2AIDS and Cancer Virus Program, Frederick National Laboratory, Frederick, MD 21702
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Michael Hull
2AIDS and Cancer Virus Program, Frederick National Laboratory, Frederick, MD 21702
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Jason Shao
3Population Sciences and Computational Biology Programs, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
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Jonah B. Sacha
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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Michael K. Axthelm
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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Paul T. Edlefsen
3Population Sciences and Computational Biology Programs, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
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Jeffrey D. Lifson
2AIDS and Cancer Virus Program, Frederick National Laboratory, Frederick, MD 21702
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Louis J. Picker
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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  • For correspondence: fruek@ohsu.edu pickerl@ohsu.edu
Klaus Früh
1Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, 97006, USA
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  • ORCID record for Klaus Früh
  • For correspondence: fruek@ohsu.edu pickerl@ohsu.edu
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Abstract

Strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens elicit CD8+ T cells that recognize peptide epitopes presented by major histocompatibility complex (MHC)-II and MHC-E molecules, instead of MHC-Ia, and are uniquely able to mediate stringent control and subsequent clearance of highly pathogenic SIV in ∼50% of vaccinated rhesus macaques (RMs). We show that the MHC-E ligand VMAPRTLLL (VL9), encoded by the Rh67 gene (or its HCMV UL40 counterpart) is required for recognition of RhCMV-infected fibroblasts by MHC-E-restricted CD8+ T cells via its ability to promote intracellular MHC-E transport. Moreover, deletion of Rh67 from 68-1 RhCMV/SIV vectors, or mutation of its embedded VL9 ligand, abrogated induction of MHC-E-restricted CD8+ T cell responses, leaving responses that exclusively target MHC-II-restricted epitopes. These MHC-II-presented CD8+ T cell responses, though comparable in response magnitude and functional differentiation to responses arising from the efficacious 68-1 vector, did not protect RMs against SIV challenge, indicating that Rh67/UL40-enabled direct priming of MHC-E-targeted CD8+ T cells is a crucial element of RhCMV/SIV vaccine efficacy.

One Sentence Summary A cytomegalovirus protein (Rh67/UL40) that upregulates MHC-E expression on RhCMV/SIV-vector infected cells is required for induction of MHC-E-restricted CD8+ T cells and for protection against SIV.

Competing Interest Statement

OHSU, SGH, LJP, and KF have a substantial financial interest in Vir Biotechnology, Inc., a company that may have a commercial interest in the results of this research and technology. SGH, LJP, and KF are also consultants to Vir Biotechnology, Inc., and JBS has received compensation for consulting for Vir Biotechnology, Inc. SGH, LJP, and KF are co-inventors of patent WO 2011 143650 A2 Recombinant RhCMV and HCMV vectors and uses thereof licensed to Vir Biotechnology, Inc. SGH, LJP, KF, and DM are co-inventors of patent US2016 0010112 A1 Cytomegalovirus vectors enabling control of T cell targeting licensed to Vir Biotechnology, Inc. SGH, LJP and KF are co-inventors of patent US2017/0143809 A1 CMV vectors comprising microRNA recognition elements licensed to Vir Biotechnology, Inc. These potential individual and institutional conflicts of interest have been reviewed and managed by OHSU.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Modulation of MHC-E transport by viral decoy ligands is required for RhCMV/SIV vaccine efficacy
Marieke Verweij, Scott G. Hansen, Ravi Iyer, Nessy John, Daniel Malouli, David Morrow, Isabel Scholz, Jennie Womack, Shaheed Abdulhaqq, Roxanne M. Gilbride, Colette M. Hughes, Abigail B. Ventura, Julia C. Ford, Andrea N. Selseth, Kelli Oswald, Rebecca Shoemaker, Brian Berkemeier, William J. Bosche, Michael Hull, Jason Shao, Jonah B. Sacha, Michael K. Axthelm, Paul T. Edlefsen, Jeffrey D. Lifson, Louis J. Picker, Klaus Früh
bioRxiv 2020.09.30.321158; doi: https://doi.org/10.1101/2020.09.30.321158
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Modulation of MHC-E transport by viral decoy ligands is required for RhCMV/SIV vaccine efficacy
Marieke Verweij, Scott G. Hansen, Ravi Iyer, Nessy John, Daniel Malouli, David Morrow, Isabel Scholz, Jennie Womack, Shaheed Abdulhaqq, Roxanne M. Gilbride, Colette M. Hughes, Abigail B. Ventura, Julia C. Ford, Andrea N. Selseth, Kelli Oswald, Rebecca Shoemaker, Brian Berkemeier, William J. Bosche, Michael Hull, Jason Shao, Jonah B. Sacha, Michael K. Axthelm, Paul T. Edlefsen, Jeffrey D. Lifson, Louis J. Picker, Klaus Früh
bioRxiv 2020.09.30.321158; doi: https://doi.org/10.1101/2020.09.30.321158

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