Page:Interim Staff Report on Investigation into Risky MPXV Experiment at the National Institute of Allergy and Infectious Diseases.pdf/68

 homeostasis contributes to the susceptibility of CAST mice to virus infection.

Gene inactivation is an important driver of orthopoxirusorthopoxvirus [sic] evolution. Whereas cowpox virus contains intact orthologs of genes present in each orthopoxvirus species, numerous genes are inactivated in all other members of the genus. Inactivation of additional genes can occur upon extensive passaging of orthopoxviruses in cell culture leading to attenuation in vivo, a strategy for making vaccines. Whether inactivation of multiple viral genes enhances replication in the host cells or has a neutral effect is unknown in most cases. Using an experimental evolution protocol involving serial passages of an attenuated vaccinia virus, rapid acquisition of inactivating frameshift mutations occurred. After only 10 passage rounds, the starting attenuated vaccinia virus was displaced by viruses with one fixed mutation and one or more additional mutations. The frequency of multiple inactivating mutations during experimental evolution simulates their acquisition during normal evolution and extensive virus passaging to make vaccine strains.

Publications Generated during the 2020 Reporting Period

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 * 1) Earl PL, Americo JL, Moss B (2020). Natural killer cells expanded in vivo or ex vivo with IL-15 overcomes the inherent susceptibility of CAST mice to lethal infection with orthopoxviruses. PLoS Pathog 16, e1008505. https://doi.org/10.1371/journal.ppat.1008505
 * 2) Liu R, Olano LR, Mirzakhanyan Y, Gershon PD, Moss B (2019). Vaccinia Virus Ankyrin-Repeat/F-Box Protein Targets Interferon-Induced IFITs for Proteasomal Degradation. Cell Rep 29, 816-828.e6. https://doi.org/10.1016/j.celrep.2019.09.039
 * 3) Senkevich TG, Zhivkoplias EK, Weisberg AS, Moss B (2019). Inactivation of Genes by Frameshift Mutations Provides Rapid Adaptation of an Attenuated Vaccinia Virus. J Virol 94. https://doi.org/10.1128/JVI.01053-20