We observed that the induction of IFN-α and TNF by myxoma virus or Heat-VAC is inhibited by co-infection with untreated WT vaccinia, but only partially attenuated when E3 is absent, or only the E3 dsRBD is produced, thus implicating the N-terminal ZBD of E3 in masking poxvirus infection from sensing by human pDCs. Here, TNF is linked to coinfection.