Mutational analysis of ORF-8 of SARS-CoV-2 -a window to immunotherapy
Cancer Research
; 82(12), 2022.
Article
in English
| EMBASE | ID: covidwho-1986482
ABSTRACT
Background:
TGF-Beta plays an important role in immune evasion in oncology. Similarly, SARSCov-2, the causal agent of the COVID-19 pandemic, also has an immune evasion function. This is mediated by ORF-8 through its interaction with multiple immune regulatory elements, including TGF-beta. This is a mutational analysis of ORF-8.Methods:
We took advantage of the database of millions of SARS-CoV-2 genomes are archived and organized in phylogenetic relationships to show the evolution of ORF-8. Site numbering and genome structure use Wuhan-Hu-1/2019 as reference. The phylogeny is rooted relative to early samples from Wuhan. Temporal resolution assumes a nucleotide substitution rate of 8 × 10-4 subs per site per year. ( https//nextstrain.org/). The epidemiological data provided at https//ourworldindata.org/coronavirus was used to determine the property of the variants using mortality and infectivity data at the site.Results:
Scan of ORF-8 revealed a high rate of mutation at aa119 and aa120. More importantly, the mutation at 120 or 119 that resulted in null ORF8 clearly delineates the pre-Delta and Delta SARSCov-2. In fact, all the delta lineages exhibited the null mutation at 119/120. This region is important for the dimerization of ORF-8 and possibly its interaction with host TGF-beta. All other variants, including the alpha variants, are wild type (aa120 = F). Monitoring the mutations over the last several months indicated that the delta variants have now picked up the wild type F at aa120 (Faa120) in Egypt or the L at aa 120 (Laa120) in India. The epidemiology of Egypt and India indicates that the Faa120 is more immune evasive and suggestive that more infectious but not more lethal.Conclusions:
This is an opportunity to monitor in real-time the evolution of ORF-8 and how it is interacting with the host immune system. Additionally, since our current clinical trial on TGF-beta inhibitors is in India and Latin America, it is an opportunity to correlate clinical findings to molecular and epidemiological data for these variants. If we are correct, the Faa120 will emerge as the dominant variant in the next wave of COVID-19.
endogenous compound; transforming growth factor beta; conference abstract; controlled study; coronavirus disease 2019; dimerization; Egypt; human; immune system; immunotherapy; India; loss of function mutation; mortality; mutational analysis; nonhuman; nucleic acid base substitution; open reading frame; phylogeny; SARS-CoV-2 (clinical isolate Wuhan/Hu-1/2019); Severe acute respiratory syndrome coronavirus 2; South and Central America; wild type
Full text:
Available
Collection:
Databases of international organizations
Database:
EMBASE
Language:
English
Journal:
Cancer Research
Year:
2022
Document Type:
Article
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