Cytomegalovirus-based vaccine vectors - the role of cytomegalovirus gH/gL/chemokine glycoprotein complexes in the vector-induced immune response

点击翻译按钮获取中文摘要

Cytomegaloviruses induce strong and lifelong effector memory T cell responses in their hosts which nevertheless do not prevent repeated superinfection with the same virus. T cell responses to foreign antigens expressed from CMV genomes can repeatedly be elicited using the same CMV vector. This makes cytomegalovirus-based vectors excellent candidates for vaccination against other viruses or for the immune therapy of tumors. All cytomegaloviruses studied so far express a viral CC chemokine which, besides modulating immune functions, additionally forms a gH/gL/chemokine glycoprotein entry complex determining the viral cell tropism. When rhesus cytomegaloviruses lacking this viral chemokine were used to express antigens from other viruses, atypical and broad CD8+ T cell responses to the antigens and an extraordinary capacity to clear those viruses were observed. Currently, it is not clear whether the observed virus clearance is dependent on those atypical CD8+ T cell responses or not. Using infection of mice with murine cytomegalovirus (MCMV) as a model, we will analyse whether deletion of the MCMV CC chemokine similarly shapes the CD8+ T cell response and whether the soluble chemokine, the gH/gL/chemokine complex, or both determine the CD8+ T cell response. Additionally, we will study whether MCMV vaccine vectors lacking or expressing the CC chemokine show different capacities to control heterologous virus infections and tumor growth and whether we can correlate immune protection and atypical CD8+ T cell responses. These studies might help to build an HCMV vector for vaccination against viruses like human immunodeficiency or hepatitis C virus or for the immune therapy of human tumors. In addition, by unraveling the mechanisms behind the high immunogenicity of modified cytomegaloviruses new ways to elicit similar T cell responses by other vaccination strategies might be found.