Hazard Characterization of Modified Vaccinia Virus Ankara Vector: What Are the Knowledge Gaps?

Okeke, Malachy I.; Okoli, Arinze S.; Diaz, Diana; Offor, Collins; Oludotun, Taiwo G.; Tryland, Morten; Bøhn, Thomas; Moens, Ugo

MVA not only depends on host pathways to successfully generate its progeny, it must also counteract inflammatory, innate and acquired immune response pathways that prevent viral replication [185] . VACV infection resulted in the activation of the Akt signaling pathway [186] . One of the Akt substrates is human cyclic guanosine monophosphate-adenosine monophosphate synthetase (cGAS). Phosphorylation of cGAS inhibits the production of type 1 IFNs and inflammatory cytokines, thereby preventing an antiviral response [187] . Hence, VACV triggered Akt activation helps the virus to evade the host defense mechanism. It is not known whether MVA infection leads to Akt activation. Another pathway that is modulated upon MVA infection is the mitogen-activated protein kinase (MAPK) pathway [188] [189] [190] . Gedey and colleagues found that MVA activates ERK1/2 in HEK293T cells [191] . This is in contrast with the findings by Schweneker et al. [188] who showed that CVA induced sustained ERK 1/2 activation in HEK293 cells but MVA failed to do so. The authors demonstrated that ERK1/2 activation depended on intact O1L gene; a gene fragmented in MVA [46] . The use of different cell lines may explain the discrepancy between the findings of these studies [188, 191] . Infection of Hela cells or mouse embryonic fibroblasts (MEFs) with MVA resulted in the upregulation of dual specificity phosphatase 1 (DUSP1), a MAPK dephosphorylating enzyme [192] . Infection of DUSP1 knockout mice with MVA enhanced the production of pro-inflammatory cytokines indicating that DUSP1 is involved in the regulation of innate and adaptive immune responses during poxvirus infection. VACV activates the MAPKs, c-Jun N-terminal protein kinase 1 and 2 (JNK1/2) [189] . Whether MVA can activate the JNK MAPK pathway was not investigated, but inhibition of this pathway causes a significant decline in virus yield in BHK-21 cells [189] .