Comparison of Crimean-Congo Hemorrhagic Fever Virus and Aigai Virus in Life Cycle Modeling Systems Reveals a Difference in L Protein Activity

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne orthonairovirus that causes a severe, often fatal, hemorrhagic disease throughout Africa, Asia, and Southeast Europe. A wide variety of strains are circulating in the field which broadly correlate to their geographic distribution. The viral determinants of pathogenicity remain unclear, as does the contribution of strain-specific differences to pathology. Aigai virus (AIGV) is a closely related virus (formally designated CCHFV genotype VI, Europe II, or AP92-like virus), which has been proposed to be less virulent than CCHFV. However, the molecular details leading to potential differences in virulence are unknown. To explore if differences exist, life cycle modeling systems, including both a minigenome and a transcriptionally competent virus-like particle assay, were developed for AIGV to allow the comparison with the CCHFV reference IbAr10200 strain. Using this approach, we could demonstrate that AIGV exhibits lower viral gene expression than the reference strain of CCHFV. Subsequent systematic exchange of viral components revealed that the L protein is responsible for the observed differences in gene expression and that the interferon (IFN) antagonistic activity of the ovarian tumor-type protease domain is not responsible for this effect. IMPORTANCE Crimean-Congo hemorrhagic fever virus (CCHFV) is the cause of severe hemorrhagic disease, which is often fatal. Present throughout Africa, Asia, and Southeast Europe, a diverse number of viral genotypes exist. However, the viral determinants of pathogenicity remain unclear. It has been proposed that the closely related Aigai virus (AIGV) may be a less virulent virus. Here, using newly developed and improved life cycle modeling systems we have examined potential differences between the CCHFV reference strain, IbAr10200, and AIGV. Using this approach, we identified lower viral gene expression driven by the AIGV viral polymerase as a major difference which may be indicative of lower virulence.