Sequestration of Late Antigens Within Viral Factories Impairs MVA Vector-Induced Protective Memory CTL Responses.

Sha Tao,Heiner Schaal,Dirk H Busch,Ronny Tao,Ingo Drexler,Marek Widera

doi:10.3389/fimmu.2019.02850

Abstract

Cytotoxic CD8+ T cell (CTL) responses play an essential role in antiviral immunity. Here, we focused on the activation of CTL which recognize epitopes derived from viral or recombinant antigens with either early or late expression kinetics after infection with Modified Vaccinia Virus Ankara (MVA). Late antigens but not early antigens failed to efficiently stimulate murine CTL lines in vitro and were unable to activate and expand protective memory T cell responses in mice in vivo. The reduced or absent presentation of late antigens was not due to impaired antigen presentation or delayed protein synthesis, but was caused by sequestration of late antigens within viral factories (VFs). Additionally, the trapping of late antigens in VFs conflicts with antigen processing and presentation as proteasomal activity was strongly reduced or absent in VFs, suggesting inefficient antigen degradation. This study gives for the first time a mechanistic explanation for the weak immunogenicity of late viral antigens for memory CTL activation. Since MVA is preferentially used as a boost vector in heterologous prime/boost vaccinations, this is an important information for future vaccine design.

Highlights

Cytotoxic CD8+ T cell (CTL) responses play an essential role in antiviral immunity by eliminating infected cells after recognition of virus-derived peptide ligands on the cell surface [1]
Using the attenuated vaccinia virus (VACV) strain Modified Vaccinia Virus Ankara (MVA), we demonstrated in the past that primary CTL responses against MVA-produced antigens were dominated by cross-priming in vivo, while infected professional antigen presenting cells, such as dendritic cells (DCs), failed to induce primary CTL [8, 25]
In order to study the processing and presentation of MVA-derived antigens which are expressed at different time points during the infectious cycle, a set of early or late genes were selected encoding antigens which contain published epitopes allowing for studies on CD8+ T cell responses (Table 3)

Summary

Introduction

Cytotoxic CD8+ T cell (CTL) responses play an essential role in antiviral immunity by eliminating infected cells after recognition of virus-derived peptide ligands on the cell surface [1]. Modified Vaccinia Virus Ankara (MVA) is a highly attenuated strain of vaccinia virus (VACV) that has lost ∼15% of the VACV genome, along with the ability to replicate in most mammalian cells [3]. It has accumulated an impressive safety and immunogenicity profile in both preclinical and clinical studies, and is being actively explored as a promising vaccine vector for a number of infectious diseases and malignancies [4, 5]. More knowledge is needed on how MVA as a replication deficient vector vaccine interacts with the host immune system, especially with dendritic cells (DCs), to induce strong immune responses [6,7,8,9]

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Conclusion