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T-00233: A Novel Arterivirus Protein and Expression Mechanism

Background: Porcine reproductive and respiratory syndrome (PRRS), a disease described in the US in 1987 and in Europe in 1990, has caused tremendous economic losses to the swine industry since its appearance, with recent costs in the US of at least $600 million annually. The etiologic agent, PRRS virus (PRRSV), was first discovered in the Netherlands in 1991 and in the US in 1992. PRRSV is a small enveloped virus in the family Arteriviridae and contains a single positive-stranded RNA genome. The genome is about 15 kb in length and contains at least ten open reading frames. The replicase genes, ORF1a and ORF1b, occupy the 5’-proximal 75% of the PRRSV genome. The pp1a and pp1ab replicase polyproteins are processed into ~14 nonstructural proteins by a complex proteolytic cascade that is directed by four proteinase domains encoded in ORF1a, which includes two papain-like cysteine proteases (PCPα and PCPβ), a cysteine protease (CP) and a serine protease (SP). The nsp2 is produced by PCPβ autocleaving between nsp1β/nsp2 and CP cleaving between nsp2/nsp3. However, an in-depth computational analysis now predicts a novel coding sequence that overlaps the nsp2 coding sequence in the +1 reading frame. The product of this overlapping coding sequence is expressed as a transframe fusion with the N-terminal region of nsp2 (termed TF for TransFrame protein), as confirmed experimentally by immunoprecipitation and western blot using TF-specific antibodies. The nsp2 region has been targeted for PRRSV vaccine and diagnostic assay development. Discovery of TF will have significant impact in these areas.

Description: The PRRSV nsp2 replicase region is being used for PRRSV diagnostics and vaccine development. The latter also includes engineered deletions and expression of foreign sequences (potentially including epitopes from other swine pathogens and/or marker epitopes to create marker vaccines).

Advantages: The discovery of a new ORF overlapping this region of the replicase gene and the efficient diversion of ribosomes into that reading frame will have an important impact on all of these areas and approaches.