Highly infectious, less pathogenic and antibody resistant Omicron XBB.1, XBB.1.5 and XBB.1.5.1-XBB.1.5.39 subvariant Coronaviruses do not produce ORF8 protein due to 8th codon GGA=TGA Termination Codon Mutation

Abstract

RNA viruses are very mutation prone. We recently reported SARS-CoV-2 ORF8 gene CAA = TAA and AAA = TAA Termination Codon Mutations in B.1.1.7 variants with no production of viable ORF8 protein. We described here another GGA = TGA termination codon in the 8th codon of ORF8 gene located exclusively in XBB.1 (XBB.1.16 and XBB.1.22) and XBB.1.5 subvariants (XBB.1.5.1 to XBB.1.5.39) but not in XBB.2 variant or Alpha, Beta, Gamma, Delta and Omicron BA.1, BA.2, BA.4, BA.5, BF.7 and BQ.1 subvariants. However, G > T mutation at 27915 also created an alternate ATG codon but the protein product was short due to preceding TAG and TGA termination codons. The originally located following ATG codons were there but in alternate reading frames and ultimately no ORF8 protein was formed in XBB.1.5 subvariants which were spreading highly now over BA.2.75, BA.4.6, BA.5.2.1, BF.7 and BQ.1.1 subvariants. This is a vivid example of three termination codon mutations in the coronavirus ORF8 protein which was implicated as target for many human proteins regulating interferon production, chromosome instability, antibody production, pathogenicity and virus clearance. The 30nt deletion in the 3’-UTR, including 24LPP, and 145Y deletions in Spike protein as well as N-protein 31ERS and ORF1ab polyprotein 3675SGF deletions made XBB.1.5 Omicron coronavirus weak and less pathogenic so that WHO declared coronaviruses as non-emergency pathogen.

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“…Further, in Delta variant, a "DF" two amino acid deletions (5'-28243GATTTC-3') in the small ORF8 protein carboxy-terminal was prominent at that locus (figure-3). Previously, we demonstrated hotspot deletion sites in the ORF7a gene and three TAA termination codons creating short chimera proteins [32][33][34]. Thus, sequence variation in that region of 3'-end of the SARS-CoV-2 may be one of the reasons of viral extinction or slower replication and pathogenicity and N-protein was implicated in replication and pathogenicity.…”

“…Thus, sequence variation in that region of 3'-end of the SARS-CoV-2 may be one of the reasons of viral extinction or slower replication and pathogenicity and N-protein was implicated in replication and pathogenicity. Indeed, downstream of N-gene, another 26nt deletion at the 3'-UTR was prominent in most omicron corona viruses [34]. Surely, such big deletion in the 3'-UTR slower viral replication and viral titre.…”

“…COVID-19 was detected in March-2019 and whole genome sequencing was available from December, 2019 onwards [2]. During three years period many mutations in the diverse variants of COVID-19 genomes were reported in the NCBI SARS-CoV-2 Database [3]. However, related SARS and MERS RNA viruses were known since 2003 and considerable molecular biology of such viruses have been reported in the PubMed [4,5].…”

“…On the country, structural spike protein is 1273aa long and other structural proteins (M, N, E) of corona virus are relatively very small [24][25][26][27][28][29]. The regulatory proteins like orf3a, orf7a, orf7b, orf8 and orf10 were also characterized having interacted with many cellular proteins [30][31][32][33][34][35]. The N-protein is a strong RNA-binding protein (419aa) and requires long structured RNA as substrate [36].…”

“…The N-protein is a strong RNA-binding protein (419aa) and requires long structured RNA as substrate [36]. Importantly, a 31ERS deletion of the protein was found in all omicron viruses including BA.2.75, BF.7, BQ.1, BQ.1.1, BQ.1.1.1 and XBB.1.5 sub subvariants [34,37]. N-protein of SARS-CoV-2 has 91% and 49% similarity to SARS-CoV and MERS-CoV respectively and is predicted to be predominantly a basic nuclear protein [38].…”