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

Unconventional answers

Rhesus cytomegalovirus (RhCMV) vectors 68-1 expressing sim immunodeficiency virus (SIV) inserts induce major histocompatibility complex E (MHC-E) – and MHC-II, limited, SIV-specific CD8+ T-responses, but the mechanisms responsible for this unconventional limitation of MHC and its contribution to the efficacy of the RhCMV / SIV vaccine are poorly known. Malouli and others. show that these responses are genetically rearranged in 68-1 RhCMVs that impair the function of eight immunomodulatory proteins encoded Rx157.5 / Rx157.4 i Rh158-161 genomic regions. Repair of each of these genes with either RhCMV or human CMV counterparts redirected responses to MHC-Ia-restricted or to a mixture of MHC-Ia- and MHC-II-restricted CD8 T cell responses, but did not protect against SIV. These data suggest that CD8 is restricted to MHC-E+ T cell responses are crucial for protection against SIV.

Summary

Insert-expressing immunodeficiency virus (SIM) virus, rhesus cytomegalovirus (RhCMV / SIV) vectors 68-1 induce major histocompatibility complex E (MHC-E) – and MHC-II, limited, SIV-specific CD8+ T cell responses, but the basis of these unconventional responses and their contribution to the proven efficacy of the SIV challenge vaccine in rhesus monkeys (RM) have not been characterized. We show that these unconventional responses are the result of a random genetic rearrangement in 68-1 RhCMV that nullified the function of eight different immunomodulatory gene products encoded in two RhCMV genomic regions (Rx157.5 / Rx157.4 i Rh158-161), revealing three patterns of inhibition of the unconventional response. Differential repair of these genes with either RhCMV derived or orthological human CMV (HCMV) sequences derived (UL128 / UL130; UL146 / UL147) leads to either of two different CD8s+ Types of T cell responses – MHC-Ia – limited to only or a combination of CD8 – MHC-II– and MHC-Ia+ T cells. Response size and functional differentiation are similar to RhCMV 68-1, but no alternative response type has mediated protection against SIV challenges. These findings imply CD8 with restriction to MHC-E+ T cell responses as mediators of anti-SIV efficacy and indicate that translating the efficacy of the RhCMV / SIV vector into humans is likely to require deletion of all genes that inhibit these responses from the HCMV / HIV vector.

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