Cytomegalovirus Vectors Violate CD8+ T Cell Epitope Recognition Paradigms

SG Hansen, JB Sacha, CM Hughes, JC Ford… - Science, 2013 - science.org
SG Hansen, JB Sacha, CM Hughes, JC Ford, BJ Burwitz, I Scholz, RM Gilbride, MS Lewis…
Science, 2013science.org
Introduction CD8+ T cell responses focus on a small fraction of total pathogen-encoded
peptides, which are similar among individuals with shared major histocompatibility complex
(MHC) alleles. This focus can limit immune control of genetically flexible pathogens, such as
HIV and SIV, because CD8+ T cells in most infected subjects do not target sequences
required for pathogen fitness, resulting in viral escape. Although a vaccine capable of
broadening or redirecting CD8+ T cell epitope targeting to prevent viral escape would be …
Introduction
CD8+ T cell responses focus on a small fraction of total pathogen-encoded peptides, which are similar among individuals with shared major histocompatibility complex (MHC) alleles. This focus can limit immune control of genetically flexible pathogens, such as HIV and SIV, because CD8+ T cells in most infected subjects do not target sequences required for pathogen fitness, resulting in viral escape. Although a vaccine capable of broadening or redirecting CD8+ T cell epitope targeting to prevent viral escape would be highly advantageous, it remains unclear whether this targeting can be diverted from its default pattern during priming.
Fibroblast-adapted RhCMV/gag vectors elicit MHC class IIâ restricted CD8+ T cells, greatly expanding the breadth of the response. (Top) Differential inhibition of SIVgag-specific CD8+ T cells from SIV+, fibroblast-adapted RhCMV/gag vectorâ vaccinated, and tropism-repaired RhCMV/gag vectorâ vaccinated rhesus macaques by MHC-I versus MHC-II blockade. (Bottom) Responses to consecutive SIVgag 15mer peptides in the indicated animals, classified by sensitivity to MHC-I versus MHC-II blockade.
Methods
We used intracellular cytokine analysis to compare the epitope targeting of SIV-specific CD8+ T cell responses in rhesus macaques with controlled SIV infection or after vaccination with either conventional SIV vaccines or rhesus cytomegalovirus (RhCMV) vectors. RhCMV vectors have been associated with stringent control of SIV challenge in the absence of protective MHC alleles.
Results
Fibroblast-adapted RhCMV/SIV vectors elicited SIV-specific CD8+ T cells that failed to target any canonical epitopes associated with SIV infection or conventional SIV vaccination. Instead, they recognized distinct epitopes characterized by extraordinary breadth (greater than that of conventional vaccines by a factor of >3), MHC class II (MHC-II) restriction (63% of epitopes), and high promiscuity (epitopes common to most or all responses in vaccinated macaques). These unconventionally targeted CD8+ T cell responses recognized autologous SIV-infected cells, indicating that processing and presentation of the unconventional epitopes is CMV-independent. However, CMV gene expression was responsible for directing epitope specificity of CD8+ T cells during priming. The induction of canonical SIV epitope–specific CD8+ T cell responses was specifically suppressed by expression of the Rh189/US11 gene, and the promiscuous MHC-I– and MHC-II–restricted CD8+ T cell responses occurred only in the absence of the Rh157.4–.6/UL128–131 genes involved in CMV tropism for nonfibroblasts.
Discussion
These findings suggest that CD8+ T cell recognition is more flexible than had been thought, and that the focused epitope recognition profiles of conventional CD8+ T cell responses may be primarily restricted by immunoregulation during priming (which can be subverted by CMV) rather than by intrinsic limitations in antigen processing/presentation or in T cell receptor repertoire. The ability of CMVs with different genetic modifications to differentially elicit CD8+ T cell responses with divergent patterns of epitope recognition raises the possibility of a CMV vector–based vaccine platform with programmable CD8+ T cell epitope targeting, including vectors that can selectively elicit CD8+ T cell responses targeting conventional or unconventional epitopes. Because the latter would be unaffected by escape mutations arising during natural infection, these vectors would be well suited for therapeutic vaccine applications.
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