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Cell Host Microbe ; 30(11): 1540-1555.e15, 2022 11 09.
Article in English | MEDLINE | ID: covidwho-2130372


The SARS-CoV-2 Omicron BA.2.75 variant emerged in May 2022. BA.2.75 is a BA.2 descendant but is phylogenetically distinct from BA.5, the currently predominant BA.2 descendant. Here, we show that BA.2.75 has a greater effective reproduction number and different immunogenicity profile than BA.5. We determined the sensitivity of BA.2.75 to vaccinee and convalescent sera as well as a panel of clinically available antiviral drugs and antibodies. Antiviral drugs largely retained potency, but antibody sensitivity varied depending on several key BA.2.75-specific substitutions. The BA.2.75 spike exhibited a profoundly higher affinity for its human receptor, ACE2. Additionally, the fusogenicity, growth efficiency in human alveolar epithelial cells, and intrinsic pathogenicity in hamsters of BA.2.75 were greater than those of BA.2. Our multilevel investigations suggest that BA.2.75 acquired virological properties independent of BA.5, and the potential risk of BA.2.75 to global health is greater than that of BA.5.

COVID-19 , SARS-CoV-2 , Humans , Antibodies, Neutralizing , Antibodies, Viral , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , COVID-19 Serotherapy
Cell Rep ; 32(12): 108185, 2020 09 22.
Article in English | MEDLINE | ID: covidwho-743905


One of the features distinguishing SARS-CoV-2 from its more pathogenic counterpart SARS-CoV is the presence of premature stop codons in its ORF3b gene. Here, we show that SARS-CoV-2 ORF3b is a potent interferon antagonist, suppressing the induction of type I interferon more efficiently than its SARS-CoV ortholog. Phylogenetic analyses and functional assays reveal that SARS-CoV-2-related viruses from bats and pangolins also encode truncated ORF3b gene products with strong anti-interferon activity. Furthermore, analyses of approximately 17,000 SARS-CoV-2 sequences identify a natural variant in which a longer ORF3b reading frame was reconstituted. This variant was isolated from two patients with severe disease and further increased the ability of ORF3b to suppress interferon induction. Thus, our findings not only help to explain the poor interferon response in COVID-19 patients but also describe the emergence of natural SARS-CoV-2 quasispecies with an extended ORF3b gene that may potentially affect COVID-19 pathogenesis.

Betacoronavirus/genetics , Coronavirus Infections/virology , Interferon Type I/antagonists & inhibitors , Pneumonia, Viral/virology , Viral Regulatory and Accessory Proteins/genetics , Adult , Amino Acid Sequence/genetics , Animals , Betacoronavirus/immunology , COVID-19 , Chiroptera/virology , Codon, Nonsense/genetics , Coronavirus Infections/pathology , Eutheria/virology , Humans , Male , Pandemics , SARS-CoV-2 , Viral Regulatory and Accessory Proteins/metabolism