The introduction of incompatibility between Junin virus Z protein and other viral proteins results in impaired replication and attenuation
Hallam, Steven Jay
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The genus Mammarenavirus with the family Arenaviridae contains many species that are pathogenic in human hosts. Among these, Junin virus (JUNV) is a New World mammarenavirus that is the causative agent of Argentine hemorrhagic fever (AHF). AHF resulted in 15-20% case fatality during epidemics until the introduction of a vaccine that drastically reduced the incidence of the disease. This live-attenuated vaccine, Candid#1 (Can), contained many amino acid divergences from wild type JUNV that may contribute to the attenuation profile. Preliminary experiments identified a natural incompatibility between the Can Z protein and wild type Romero (Rom) strain LP that was not seen in Can Z and Can LP. Characterization of this incompatibility demonstrated reduced growth and replication in rJUNV harboring Can Z and Rom LP. When characterized in the in vivo guinea pig model, the CanZ/RomLP mismatch resulted in attenuation of the virus and a pathology profile similar to rCan. In addition, it was narrowed down to a single mutation (V64G) within the Z that conferred the attenuation when paired with Rom LP. The LP is comprised of four domains. We generated chimeric LPs representing permutations of Can and Rom to determine which Rom domain exhibited an incompatibility with Can Z. The in vitro characterization results of these chimeric proteins indicated that both domains I and III likely contribute to incompatibility with Can Z. These studies characterize a novel attenuation method for JUNV utilizing the Z protein in addition to elucidating further mechanisms caused by Z incompatibility.