Viral Sequestration of Antigen Subverts Cross Priming (93.14)

Abstract

Abstract Antigens driven by poxvirus late promoters are produced in much larger quantities than those driven by early promoters both in vitro and in vivo. Despite the abundance of protein produced, antigens driven by late poxvirus promoters typically induce a low or undetectable CD8+ T cell response following immunization in vivo, while those driven by early promoters induce a significant response. We show that antigen driven by late promoters is not expressed in primary dendritic cells, preventing induction of naïve CD8+ T cells via the direct presentation pathway. However, it is puzzling why the cross priming pathway does not compensate for this lack of direct presentation as the relevance of the pathway is based upon its ability to induce CD8+ T cells in the absence of viral infection of DC or upon the expression of viral modulatory molecules that may prevent direct presentation. Our studies demonstrate that when present in similar quantities, late promoter driven antigen is not available for cross priming in vivo. In contrast, cellular antigen from virus-infected cells can access the cross priming pathway under comparable conditions. The mechanism involved does not require the shutoff of host cell protein synthesis but is due to the sequestration of late promoter driven antigen in viral factories inhibiting antigen donation to DC. This observation indicates a novel mechanism of viral evasion, whereby antigen is not available for use in either the direct or cross priming pathways.