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

Marieke C. 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

doi:10.1126/science.abe9233

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

Marieke C. 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 ShaoJonah B. Sacha, Michael K. Axthelm, Paul T. Edlefsen, Jeffrey D. Lifson, Louis J. Picker, Klaus Früh

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Abstract

Strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens elicit CD8⁺ T cells recognizing epitopes presented by major histocompatibility complex II (MHC-II) and MHC-E but not MHC-Ia. These immune responses mediate replication arrest of SIV in 50 to 60% of monkeys. We show that the peptide VMAPRTLLL (VL9) embedded within the RhCMV protein Rh67 promotes intracellular MHC-E transport and recognition of RhCMV-infected fibroblasts by MHC-E-restricted CD8⁺ T cells. Deletion or mutation of viral VL9 abrogated MHC-E-restricted CD8⁺ T cell priming, resulting in CD8⁺ T cell responses exclusively targeting MHC-II-restricted epitopes. These responses were comparable in magnitude and differentiation to responses elicited by 68-1 vectors but did not protect against SIV. Thus, Rh67-enabled direct priming of MHC-E-restricted T cells is crucial for RhCMV/SIV vaccine efficacy.

Original language	English (US)
Article number	eabe9233
Journal	Science
Volume	372
Issue number	6541
DOIs	https://doi.org/10.1126/science.abe9233
State	Published - Apr 30 2021

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Verweij, M. C., Hansen, S. G., Iyer, R., John, N., Malouli, D., Morrow, D., Scholz, I., Womack, J., Abdulhaqq, S., Gilbride, R. M., Hughes, C. M., Ventura, A. B., Ford, J. C., Selseth, A. N., Oswald, K., Shoemaker, R., Berkemeier, B., Bosche, W. J., Hull, M., ... Früh, K. (2021). Modulation of MHC-E transport by viral decoy ligands is required for RhCMV/SIV vaccine efficacy. Science, 372(6541), Article eabe9233. https://doi.org/10.1126/science.abe9233

Verweij, MC, Hansen, SG, Iyer, R, John, N, Malouli, D, Morrow, D, Scholz, I, Womack, J, Abdulhaqq, S, Gilbride, RM, Hughes, CM, Ventura, AB, Ford, JC, Selseth, AN, Oswald, K, Shoemaker, R, Berkemeier, B, Bosche, WJ, Hull, M, Shao, J, Sacha, JB , Axthelm, MK, Edlefsen, PT, Lifson, JD, Picker, LJ & Früh, K 2021, 'Modulation of MHC-E transport by viral decoy ligands is required for RhCMV/SIV vaccine efficacy', Science, vol. 372, no. 6541, eabe9233. https://doi.org/10.1126/science.abe9233

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

abstract = "Strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens elicit CD8+ T cells recognizing epitopes presented by major histocompatibility complex II (MHC-II) and MHC-E but not MHC-Ia. These immune responses mediate replication arrest of SIV in 50 to 60% of monkeys. We show that the peptide VMAPRTLLL (VL9) embedded within the RhCMV protein Rh67 promotes intracellular MHC-E transport and recognition of RhCMV-infected fibroblasts by MHC-E-restricted CD8+ T cells. Deletion or mutation of viral VL9 abrogated MHC-E-restricted CD8+ T cell priming, resulting in CD8+ T cell responses exclusively targeting MHC-II-restricted epitopes. These responses were comparable in magnitude and differentiation to responses elicited by 68-1 vectors but did not protect against SIV. Thus, Rh67-enabled direct priming of MHC-E-restricted T cells is crucial for RhCMV/SIV vaccine efficacy.",

author = "Verweij, {Marieke C.} and Hansen, {Scott G.} and Ravi Iyer and Nessy John and Daniel Malouli and David Morrow and Isabel Scholz and Jennie Womack and Shaheed Abdulhaqq and Gilbride, {Roxanne M.} and Hughes, {Colette M.} and Ventura, {Abigail B.} and Ford, {Julia C.} and Selseth, {Andrea N.} and Kelli Oswald and Rebecca Shoemaker and Brian Berkemeier and Bosche, {William J.} and Michael Hull and Jason Shao and Sacha, {Jonah B.} and Axthelm, {Michael K.} and Edlefsen, {Paul T.} and Lifson, {Jeffrey D.} and Picker, {Louis J.} and Klaus Fr{\"u}h",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.",

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doi = "10.1126/science.abe9233",

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AU - Verweij, Marieke C.

AU - Hansen, Scott G.

AU - Iyer, Ravi

AU - John, Nessy

AU - Malouli, Daniel

AU - Morrow, David

AU - Scholz, Isabel

AU - Womack, Jennie

AU - Abdulhaqq, Shaheed

AU - Gilbride, Roxanne M.

AU - Hughes, Colette M.

AU - Ventura, Abigail B.

AU - Ford, Julia C.

AU - Selseth, Andrea N.

AU - Oswald, Kelli

AU - Shoemaker, Rebecca

AU - Berkemeier, Brian

AU - Bosche, William J.

AU - Hull, Michael

AU - Shao, Jason

AU - Sacha, Jonah B.

AU - Axthelm, Michael K.

AU - Edlefsen, Paul T.

AU - Lifson, Jeffrey D.

AU - Picker, Louis J.

AU - Früh, Klaus

PY - 2021/4/30

Y1 - 2021/4/30

N2 - Strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens elicit CD8+ T cells recognizing epitopes presented by major histocompatibility complex II (MHC-II) and MHC-E but not MHC-Ia. These immune responses mediate replication arrest of SIV in 50 to 60% of monkeys. We show that the peptide VMAPRTLLL (VL9) embedded within the RhCMV protein Rh67 promotes intracellular MHC-E transport and recognition of RhCMV-infected fibroblasts by MHC-E-restricted CD8+ T cells. Deletion or mutation of viral VL9 abrogated MHC-E-restricted CD8+ T cell priming, resulting in CD8+ T cell responses exclusively targeting MHC-II-restricted epitopes. These responses were comparable in magnitude and differentiation to responses elicited by 68-1 vectors but did not protect against SIV. Thus, Rh67-enabled direct priming of MHC-E-restricted T cells is crucial for RhCMV/SIV vaccine efficacy.

AB - Strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens elicit CD8+ T cells recognizing epitopes presented by major histocompatibility complex II (MHC-II) and MHC-E but not MHC-Ia. These immune responses mediate replication arrest of SIV in 50 to 60% of monkeys. We show that the peptide VMAPRTLLL (VL9) embedded within the RhCMV protein Rh67 promotes intracellular MHC-E transport and recognition of RhCMV-infected fibroblasts by MHC-E-restricted CD8+ T cells. Deletion or mutation of viral VL9 abrogated MHC-E-restricted CD8+ T cell priming, resulting in CD8+ T cell responses exclusively targeting MHC-II-restricted epitopes. These responses were comparable in magnitude and differentiation to responses elicited by 68-1 vectors but did not protect against SIV. Thus, Rh67-enabled direct priming of MHC-E-restricted T cells is crucial for RhCMV/SIV vaccine efficacy.

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

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