Cytomegalovirus Vectors Violate CD8 ⁺ T Cell Epitope Recognition Paradigms

Abstract

CD8+ T cell responses focus on a small fraction of pathogen- or vaccine-encoded peptides, and for some pathogens, these restricted recognition hierarchies limit the effectiveness of anti-pathogen immunity. We found that simian immunodeficiency virus (SIV) protein-expressing Rhesus Cytomegalovirus (RhCMV) vectors elicit SIV-specific CD8+ T cells that recognize unusual, diverse and highly promiscuous epitopes, including dominant responses to epitopes restricted by class II major histocompatibility complex (MHC) molecules. Induction of canonical SIV epitope-specific CD8+ T cell responses is suppressed by the RhCMV-encoded Rh189 (US11) gene, and the promiscuous MHC class I- and class II-restricted CD8+ T cell responses only occur in the absence of the Rh157.4-.6 (UL128-131) genes. Thus, CMV vectors can be genetically programmed to achieve distinct patterns of CD8+ T cell epitope recognition.

The (gradual) rise of memory inflation

“…These fit well with the slightly updated version of the definition included in this review. For the rhesus macaque‐based cytomegaloviruses, there are a series of additional modifications regarding immune evasion and, interestingly, cellular targeting which can have quite profound impacts on the specificities observed, some of which are unconventional (eg, HLA‐E restricted) and can have potentially potent antiviral properties 86, 87, 88. Overall—even in settings where more conventional CD8 + T‐cell responses are induced—there is evidence that these responses can provide protection against viruses and cancers 2, 43.…”

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

“…On the other hand, Hansen et al 90 , 91 reported no protection from virus acquisition but found robust control of viremia in ∼half of the rCMV (SIV Gag) immunized macaques. A fundamental difference between our and the rCMV vaccine is that DNA vaccination induces T cell immunity using canonical MHC molecules, while certain rCMV vectors are able to elicit T cell immunity through the non-canonical MHC-E, 94 , 95 a feature that makes the rCMV vector induced responses unique. In a study designed to mimick elite controllers, Mudd et al 69 reported that vaccination of Mamu B*08 + macaques with recombinant yellow fever 17D (rYF17D)/rAd5 vectors expressing three Mamu B*08 restricted Nef and Vif CD8 epitopes resulted in efficient control of viremia.…”

Polyvalent vaccine approaches to combat HIV‐1 diversity

“…A novel CMV vector developed by Louis Picker et al 31, 32, 33. has elicited unusual and protective T‐cell responses in rhesus macaques.…”

“…By using rhesus CMV vectors that lacked particular genes (Rh157.5, Rh157.4, and Rh157.6), a prolific T‐cell response was generated, and a very high density of epitopes was targeted in the SIVmac Gag protein that was included in the vaccine. The responses were restricted either by class II major histocompatibility complex (MHC) molecules,32 or by the conserved, non‐classical, ubiquitously expressed MHC‐E protein 33. The MHC‐E presented epitopes were non‐canonical, meaning that they generally did not contain previously defined MHC‐E anchor motifs 33.…”

“…The responses were restricted either by class II major histocompatibility complex (MHC) molecules,32 or by the conserved, non‐classical, ubiquitously expressed MHC‐E protein 33. The MHC‐E presented epitopes were non‐canonical, meaning that they generally did not contain previously defined MHC‐E anchor motifs 33. The biology underlying this highly unusual protection is not yet understood, but if the uncharacteristically large number of CTL responses induced by the rhCMV vectors contribute to the protection, designing HIV inserts that are likely to produce a large number of cross‐reactive responses may be important for vaccine success.…”