MERS coronaviruses from camels in Africa exhibit region-dependent genetic diversity

Chu, Daniel K. W.; Hui, Kenrie P. Y.; Perera, Ranawaka A. P. M.; Miguel, Eve; Niemeyer, Daniela; Zhao, Jincun; Channappanavar, Rudragouda; Dudas, Gytis; Oladipo, Jamiu O.; Traoré, Amadou; Fassi-Fihri, Ouafaa; Ali, Abraham; Demissié, Getnet F.; Muth, Doreen; Chan, Michael C. W.; Nicholls, John M.; Meyerholz, David K.; Kuranga, Sulyman A.; Mamo, Gezahegne; Zhou, Ziqi; So, Ray T. Y.; Hemida, Maged G.; Webby, Richard J.; Roger, Francois; Rambaut, Andrew; Poon, Leo L. M.; Perlman, Stanley; Drosten, Christian; Chevalier, Veronique; Peiris, Malik

Taken together, our data suggest that BF785 and Nig1657 have reduced replication competence in Calu-3 cells and in ex vivo cultures of human bronchus and lung and, in the case of BF785, also have reduced replication competence in Ad5-hDPP4-transduced mice (comparable experiments were not carried out with Nig1657). Although these viruses have deletions in ORF4b, this does not appear to be the major explanation for the reduced viral replication competence of clade C1 viruses. It is relevant that two clade B viruses, Riyadh_1_2012 and Bisha_1_2012, which also have ORF4b deletions, have previously been isolated from patients with severe human disease. Thus, ORF4b deletions by themselves are unlikely to contribute to altered zoonotic transmission of West African viruses. Furthermore, in previous experiments where EMC virus has been serially passaged in mice to derive mouse-adapted MERS-CoV, such mouse adaptation and increase in virulence for mice have often been associated with deletions or frameshift mutations in all the accessory proteins, including ORF5 (19, 20) . Recently, a clade B MERS-CoV with a deletion in ORF4a (a different accessory gene) and a minor deletion in ORF3 has been isolated from humans diagnosed as part of a hospital outbreak in Jordan (21) . All 13 viruses from patients sampled during this outbreak had this ORF4a deletion, indicating that these viruses were transmissible in humans. ORF4a is also known to be an IFN antagonist acting by binding and antagonizing the dsRNA-binding protein PACT (22) . It is not yet reported whether ORF4a deletions in these human MERS-CoV affect IFN responses or virus replication competence.