Research ArticleHIV

Cytomegaloviral determinants of CD8+ T cell programming and RhCMV/SIV vaccine efficacy

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Science Immunology  25 Mar 2021:
Vol. 6, Issue 57, eabg5413
DOI: 10.1126/sciimmunol.abg5413

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Unconventional responses

The 68-1 rhesus cytomegalovirus (RhCMV) vectors that express simian immunodeficiency virus (SIV) inserts induce major histocompatibility complex E (MHC-E)– and MHC-II–restricted, SIV-specific CD8+ T cell responses, but the mechanisms responsible for this unconventional MHC restriction and its contribution to RhCMV/SIV vaccine efficacy are poorly understood. Malouli et al. show that these responses result from genetic rearrangements in 68-1 RhCMV that disrupt the function of eight immunomodulatory proteins encoded by the Rh157.5/Rh157.4 and Rh158-161 genomic regions. Repair of each of these genes with either RhCMV or human CMV counterparts shifted responses to an MHC-Ia–restricted or a mixture of MHC-Ia– and MHC-II–restricted CD8 T cell responses but did not protect against SIV. These data suggest that MHC-E–restricted CD8+ T cell responses are critical to protection against SIV.

Abstract

Simian immunodeficiency virus (SIV) insert–expressing, 68-1 rhesus cytomegalovirus (RhCMV/SIV) vectors elicit major histocompatibility complex E (MHC-E)– and MHC-II–restricted, SIV-specific CD8+ T cell responses, but the basis of these unconventional responses and their contribution to demonstrated vaccine efficacy against SIV challenge in the rhesus monkeys (RMs) have not been characterized. We show that these unconventional responses resulted from a chance genetic rearrangement in 68-1 RhCMV that abrogated the function of eight distinct immunomodulatory gene products encoded in two RhCMV genomic regions (Rh157.5/Rh157.4 and Rh158-161), revealing three patterns of unconventional response inhibition. Differential repair of these genes with either RhCMV-derived or orthologous human CMV (HCMV)–derived sequences (UL128/UL130; UL146/UL147) leads to either of two distinct CD8+ T cell response types—MHC-Ia–restricted only or a mix of MHC-II– and MHC-Ia–restricted CD8+ T cells. Response magnitude and functional differentiation are similar to RhCMV 68-1, but neither alternative response type mediated protection against SIV challenge. These findings implicate MHC-E–restricted CD8+ T cell responses as mediators of anti-SIV efficacy and indicate that translation of RhCMV/SIV vector efficacy to humans will likely require deletion of all genes that inhibit these responses from the HCMV/HIV vector.

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