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Venezuelan equine encephalitis virus (VEEV) is one of the important human and animal pathogens. It forms replication enzyme complexes (RCs) containing viral nonstructural proteins (nsPs) that mediate the synthesis of virus-specific RNAs. The assembly and associated functions of RC also depend on the presence of a specific set of host proteins. Our study demonstrates that the hypervariable domain (HVD) of VEEV nsP3 interacts with the members of the FXR family of cellular proteins and also binds the Src homology 3 (SH3) domain-containing proteins CD2AP and SH3KBP1. Interactions with FXR family members are mediated by the C-terminal repeating peptide of HVD. A single short, minimal motif identified in this study is sufficient for driving efficient VEEV replication in the absence of HVD interactions with other host proteins. The SH3 domain-containing proteins bind to another fragment of VEEV HVD. They can promote viral replication in the absence of FXR-HVD interactions albeit less efficiently. VEEV replication can be also switched from an FXR-dependent to a chikungunya virus-specific, G3BP-dependent mode. The described modifications of VEEV HVD have a strong impact on viral replication in vitro and pathogenesis. Their effects on viral pathogenesis depend on mouse age and the genetic background of the virus. IMPORTANCE The replication of alphaviruses is determined by specific sets of cellular proteins, which mediate the assembly of viral replication complexes. Some of these critical host factors interact with the hypervariable domain (HVD) of alphavirus nsP3. In this study, we have explored binding sites of host proteins, which are specific partners of nsP3 HVD of Venezuelan equine encephalitis virus. We also define the roles of these interactions in viral replication both in vitro and in vivo A mechanistic understanding of the binding of CD2AP, SH3KBP1, and FXR protein family members to VEEV HVD uncovers important aspects of alphavirus evolution and determines new targets for the development of alphavirus-specific drugs and directions for viral attenuation and vaccine development.

Mutations in Hypervariable Domain of Venezuelan Equine Encephalitis Virus nsP3 Protein Differentially Affect Viral Replication