SARS-CoV-2 variants evolve convergent strategies to remodel the host response

SARS-CoV-2 variants of concern (VOCs) emerged during the COVID-19 pandemic. Here, we used unbiased systems approaches to study the host-selective forces driving VOC evolution. We discovered that VOCs evolved convergent strategies to remodel the host by modulating viral RNA and protein levels, altering viral and host protein phosphorylation, and rewiring virus-host protein-protein interactions. Integrative computational analyses revealed that although Alpha, Beta, Gamma, and Delta ultimately converged to suppress interferon-stimulated genes (ISGs), Omicron BA.1 did not. ISG suppression correlated with the expression of viral innate immune antagonist proteins, including Orf6, N, and Orf9b, which we mapped to specific mutations. Later Omicron subvariants BA.4 and BA.5 more potently suppressed innate immunity than early subvariant BA.1, which correlated with Orf6 levels, although muted in BA.4 by a mutation that disrupts the Orf6-nuclear pore interaction. Our findings suggest that SARS-CoV-2 convergent evolution overcame human adaptive and innate immune barriers, laying the groundwork to tackle future pandemics. [Display omitted] •Systems analyses reveal the host-selective forces that drive SARS-CoV-2 evolution•Variants modulate viral protein levels, phosphorylation, and virus-host complexes•Variants converge on innate immune suppression by modulating viral proteins•Understanding innate/adaptive immune balance will aid future pandemic preparedness Systems proteomic and genomic analyses reveal that SARS-CoV-2 variants of concern respond to the selective forces of the host immune response by modulating viral protein expression, phosphorylation, and virus-host protein-protein interactions. Variants have converged on similar strategies for innate and adaptive immune evasions, suggesting implications for predicting viral transmission and tackling future viral pandemics.