Veterinary Research, a journal on Animal Infection

The untranslated regions (UTRs) of the foot-and-mouth disease virus (FMDV) genome contain multiple functional elements. In the 5′ UTR, the internal ribosome entry site (IRES) element governs cap-independent translation initiation, whereas the S region is presumably involved in RNA replication. The 3′ UTR, composed of two stem–loops and a poly(A) tract, is required for viral infectivity and stimulates IRES activity. Here, it was found that the 3′ end established two distinct strand-specific, long-range RNA–RNA interactions, one with the S region and another with the IRES element. These interactions were not observed with the 3′ UTR of a different picornavirus. Several results indicated that different 3′ UTR motifs participated in IRES or S region interactions. Firstly, a high-order structure adopted by both the entire IRES and the 3′ UTR was essential for RNA interaction. In contrast, the S region interacted with each of the stem–loops. Secondly, S–3′ UTR interaction but not IRES–3′ UTR interaction was dependent on a poly(A)-dependent conformation. However, no other complexes were observed in mixtures containing the three transcripts, suggesting that these regions did not interact simultaneously with the 3′ UTR probe. Cellular proteins have been found to bind the S region and one of these also binds to the 3′ UTR in a competitive manner. Our data suggest that 5′–3′-end bridging through both direct RNA–RNA contacts and RNA–protein interactions may play an essential role in the FMDV replication cycle.

The 3′ noncoding region (NCR) of the genomic picornaviral RNA is believed to contain majorcis-acting signals required for negative-strand RNA synthesis. The 3′ NCR of foot-and-mouth disease virus (FMDV) was studied in the context of a full-length infectious clone in which the genetic element was deleted or exchanged for the equivalent region of a distantly related swine picornavirus, swine vesicular disease virus (SVDV). Deletion of the 3′ NCR, while maintaining the intact poly(A) tail as well as its replacement for the SVDV counterpart, abrogated virus replication in susceptible cells as determined by infectivity and Northern blot assays. Nevertheless, the presence of the SVDV sequence allowed the synthesis of low amounts of chimeric viral RNA at extended times post-transfection as compared to RNAs harbouring the 3′ NCR deletion. The failure to recover viable viruses or revertants after several passages on susceptible cells suggests that the presence of specific sequences contained within the FMDV 3′ NCR is essential to complete a full replication cycle and that FMDV and SVDV 3′ NCRs are not functionally interchangeable.

Foot-and-mouth disease virus (FMDV) is the causative agent of an acute vesicular disease affecting pigs, cattle and other domestic and wild animals worldwide. The aim of the host interferon (IFN) response is to limit viral replication and spread. Detection of the viral genome and products by specialized cellular sensors initiates a signaling cascade that leads to a rapid antiviral response involving the secretion of type I- and type III-IFNs and other antiviral cytokines with antiproliferative and immunomodulatory functions. During co-evolution with their hosts, viruses have acquired strategies to actively counteract host antiviral responses and the balance between innate response and viral antagonism may determine the outcome of disease and pathogenesis. FMDV proteases Lpro and 3C have been found to antagonize the host IFN response by a repertoire of mechanisms. Moreover, the putative role of other viral proteins in IFN antagonism is being recently unveiled, uncovering sophisticated immune evasion strategies different to those reported to date for other members of the Picornaviridae family. Here, we review the interplay between antiviral responses induced by FMDV infection and viral countermeasures to block them. Research on strategies used by viruses to modulate immunity will provide insights into the function of host pathways involved in defense against pathogens and will also lead to development of new therapeutic strategies to fight virus infections.