Article: article from journal or magazin.
Innate and adaptive immune control of genetically engineered live-attenuated arenavirus vaccine prototypes.
Arenaviruses such as Lassa virus (LASV) cause significant morbidity and mortality in endemic areas. Using a glycoprotein (GP) exchange strategy, we have recently developed live-attenuated arenavirus vaccine prototypes (rLCMV/VSVG) based on lymphocytic choriomeningitis virus (LCMV), a close relative of LASV. rLCMV/VSVG induced long-term CD8(+) T cell immunity against wild-type virus challenge and exhibited a stably attenuated phenotype in vivo. Here we elucidated the innate and adaptive immune requirements for the control of rLCMV/VSVG. Infection of RAG(-/-) mice resulted in persisting viral RNA in blood but not in overt viremia. The latter was only found in mice lacking both RAG and IFN type I receptor. Conversely, absence of IFN type II signaling or NK cells on an RAG-deficient background had only minor effects on vaccine virus load or none at all. rLCMV/VSVG infection of wild-type mice induced less type I IFN than did wild-type LCMV, and type I as well as type II IFNs were dispensable for the induction of virus-specific memory CD8 T cells and virus-neutralizing antibodies by rLCMV/VSVG. In conclusion, the adaptive immune systems are essential for elimination of rLCMV/VSVG, and type I but not type II IFN plays a major contributive role in lowering rLCMV/VSVG loads in vivo, attesting to the attenuation profile of the vaccine. Nevertheless, IFNs are not required for the induction of potent vaccine responses. These results provide a better understanding of the immunobiology of rLCMV/VSVG and will contribute to the further development of GP exchange vaccines for combating arenaviral hemorrhagic fevers.
Adaptive Immunity, Animals, CD8-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/metabolism, Genes, RAG-1/genetics, Immunity, Innate, Immunologic Memory, Lassa Fever/immunology, Lassa Fever/prevention & control, Lassa virus/immunology, Lassa virus/pathogenicity, Mice, Mice, Inbred C57BL, Organisms, Genetically Modified, Receptor, Interferon alpha-beta/genetics, Receptor, Interferon alpha-beta/immunology, Receptors, Interferon/genetics, Receptors, Interferon/immunology, Vaccines, Attenuated, Viral Vaccines
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