Comparative genomic analysis of pre-epidemic and epidemic Zika virus strains for virological factors potentially associated with the rapidly expanding epidemic

Zhu, Zheng; Chan, Jasper Fuk-Woo; Tee, Kah-Meng; Choi, Garnet Kwan-Yue; Lau, Susanna Kar-Pui; Woo, Patrick Chiu-Yat; Tse, Herman; Yuen, Kwok-Yung

NS2A, NS2B, NS4A and NS4B of flaviviruses are small, hydrophobic proteins with incompletely understood functions and no known enzymatic motifs. 19 Each of these proteins has two or more membrane-spanning regions and may play important roles in the assembly or anchoring of the viral replication complexes on the Comparative genomic analysis of Zika virus Z Zhu et al endoplasmic reticular membrane. 52, 53 Mutation at the helix-breaker amino acid R84 at the NS2A of WNV may attenuate viral replication. 19 NS2B interacts with the NS3 C-terminal protease domain to form the viral serine protease complex that is involved in the cleavage of the viral polyprotein. Moreover, these NS proteins may exert important effects on the host immune response. The DENV NS2B/NS3 complex has been shown to mediate cleavage of STING, which is a key mediator in the pathways of the host innate immune response. 54 Expression of WNV and Kunjin virus NS2A, NS2B, NS4A and NS4B proteins may also block type I interferon signaling. 55, 56 Mutations at the NS4B of WNV may attenuate the neurovirulence and viral replication in infected mice. 57, 58 We found two amino acid substitutions that are present in all the epidemic strains, including V2449I and L2451S, among the analyzed ZIKV strains ( Figure 2C ). Interestingly, we also found that there is likely a recombination between the NS2B of ZIKV and SPOV, although the direction of gene transfer was uncertain (Figures 3 and 4) . A recent study did not detect recombination events between the epidemic Brazilian ZIKV strain and other arboviruses including DENV-1, DENV-4, WNV, YFV and Chikungunya virus, but SPOV was not included in the analysis. 10 Further investigations are necessary to determine the biological significance of these amino acid substitutions among the ZIKV strains and this recombination between the two human-pathogenic mosquito-borne flaviviruses.