ORF1a

ORF1a is a large open reading frame at the 5' end of coronavirus genomes. It is responsible for encoding the non-structural polyprotein pp1a, which forms the basis of the viral replication machinery. Alongside ORF1b, which encodes additional non-structural proteins, ORF1a participates in producing the full replicase complex through a programmed ribosomal frameshift event that generates the larger ORF1ab polyprotein in many viruses.

During translation, the ORF1a region is read by host ribosomes to produce pp1a. A -1 ribosomal frameshift at the ORF1a/ORF1b junction allows a subset of ribosomes to continue into ORF1b, yielding the extended pp1ab polyprotein. The resulting polyproteins (pp1a and pp1ab) are then proteolytically processed by viral proteases to release 11 non-structural proteins (nsps 1–11) from the ORF1a portion.

Proteolytic processing is carried out by two main viral proteases: the papain-like protease activity within nsp3 (PLpro) and the 3C-like protease activity within nsp5 (3CLpro). The mature nsps assemble into the replication-transcription complex (RTC) that carries out viral RNA synthesis and the production of subgenomic RNAs used to express structural and accessory proteins. The nsps include key enzymes such as the RNA-dependent RNA polymerase (nsp12), helicase (nsp13), and proofreading exonuclease (nsp14), among others, which together support replication, transcription, and genome maintenance.

ORF1a is highly conserved among coronaviruses and is essential for replication, serving as the source of the initial non-structural components that drive the viral life cycle.