Grossi-Soyster, E. N.; Gullberg, R. C.; Rustagi, A.; Lee, J. S.; Blish, C. A.; Cherry, S.; Salzman, J.; Sarnow, P.

Virus-derived circular RNA molecules (VcircRNAs) are expressed by many RNA viruses during infection. Putative functions include modulating viral replication and interacting with the host immune response. Some function as non-coding RNA fragments that regulate gene expression through binding to complementary RNA sequences, whereas others contain internal ribosomal entry site (IRES) sequences or non-canonical modifications that allow them to be translated. Here, we confirm the expression of a distinct SARS-CoV-2 VcircRNA molecule, circ7b8N, that has not been previously identified. We found that circ7b8N is expressed and detectable in cell culture infections and in acute infections across SARS-CoV-2 variants and shows promise for detection in post-acute clinical samples. Conservation of circ7b8N junctions is limited to the nearest phylogenetic relatives within the betacoronavirus genus but are present in other human and bat-infecting coronaviruses. Host cell gene expression is modulated by the treatment with circ7b8N agnostic of viral infection. The discovery and subsequent confirmation of circ7b8N expressed by SARS-CoV-2 provides a new biomarker for infection, and its conservation across variants suggests functional importance.