RNA Viruses: RNA Roles in Pathogenesis, Coreplication and Viral Load

Poltronieri, Palmiro; Sun, Binlian; Mallardo, Massimo

Several RNA secondary structures have been shown important for the virus functions: internal ribosomal entry structure, internal ribosomal entry site, and 5' UTRs regulate the start of translation of operons. For example, in influenza virus type C, there are seven vRNA segments with noncoding regions (NCR) at the extremities, that affects transcription and replication, by the type-C and type-A polymerase complexes [19] . To determine the molecular structure adopted by these NCR, various bioinformatics tools, including RNAfold, RNAstructure, Sfold, and Mfold, have been used. Various nucleotide polymorphisms (SNPs) in these non-coding regions may differentiate infective strains, such as major or minor read-through activity and differential expression of ORFs in operons. In Orthomyxoviridae, such as human influenza viruses or infective salmon anemia virus (ISAV), studies suggest an association between the molecular architecture of NCR regions and their role in the viral life cycle [20] . The 3' and 5'-terminal sequences of influenza A, B and C virus RNA segments are highly conserved and show partial inverted complementarity [21] . The viral RNA 3'and 5'-end structure and mRNA transcription of infectious salmon anaemia virus resemble those of influenza viruses [22] . The aligned Non-Coding Region (NCR) sequences from ISAV isolates were compared with those from influenza virus, and consensus sequences were found, based on conserved regions identified in the consensus sequence [23] . This hypothetical structure, together with a comparison with influenza viruses, yielded reliable secondary structure models that lead to identification of conserved nucleotide positions at inter-genus level to determine which nucleotide positions are involved in the recognition of the vRNA/cRNA by RNA-dependent RNA polymerase (RdRp) or mRNA by the ribosome. The NCR contain conserved sequences that vary in length among the various genera of the family Orthomyxoviridae [24] . It has been reported that the first 12 and 13 nucleotides correspond to conserved sequences in the 3' and 5' ends, respectively, of all segments of the influenza A vRNA [25] . Structurally, these conserved sequences in influenza A have been described as partially complementary and capable of interacting in cis within each segment of RNA, forming structures called panhandles [26, 27] In Orthomyxoviruses, transcription of the genome requires the vRNA to act as template for each genomic segment, and for transcription to occur, the conformation adopted via the folding of the NCR is essential [26] .