Complex signals in the genomic 3′ nontranslated region of bovine viral diarrhea virus coordinate translation and replication of the viral RNA

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Abstract
The genomes of positive-strand RNA viruses strongly resemble cellular mRNAs. However, besides operating as a messenger to generate the virus-encoded proteins, the viral RNA serves also as a template during replication. A central issue of the viral life cycle, the coordination of protein and RNA synthesis, is yet poorly understood. Examining bovine viral diarrhea virus (BVDV), we report here on the role of the variable 3′V portion of the viral 3′ nontranslated region (3′NTR). Genetic studies and structure probing revealed that 3′V represents a complex RNA motif that is composed of synergistically acting sequence and structure elements. Correct formation of the 3′V motif was shown to be an important determinant of the viral RNA replication process. Most interestingly, we found that a proper conformation of 3′V is required for accurate termination of translation at the stop-codon of the viral open reading frame and that efficient termination of translation is essential for efficient replication of the viral RNA. Within the viral 3′NTR, the complex 3′V motif constitutes also the binding site of recently characterized cellular host factors, the so-called NFAR proteins. Considering that the NFAR proteins associate also with the 5′NTR of the BVDV genome, we propose a model where the viral 3′NTR has a bipartite functional organization: The conserved 3′ portion (3′C) is part of the nascent replication complex; the variable 5′ portion (3′V) is involved in the coordination of the viral translation and replication. Our data suggest the accuracy of translation termination as a sophisticated device determining viral adaptation to the host.