Removal of vaccinia virus genes that block interferon type I and II

27 Poxviruses encode multiple inhibitors of the interferon (IFN) system, acting at different 28 levels and blocking the induction of host defence mechanisms. Two viral gene products 29 B19 and B8 have been shown to act as decoy receptors of type I and type II IFN, 30 blocking the binding of IFN to its receptor. Since IFN plays a major role in innate 31 immune responses, in this investigation we have asked the question as to what extent 32 the viral inhibitors of the IFN system impact on the capacity of poxvirus vectors to 33 activate the immune responses. This has been tested in a mouse model with single 34 and double deletion mutants of the vaccine candidate NYVAC-C that express the HIV-1 35 Env, Gag, Pol and Nef antigens. When deleted individually or in double, the type I 36 (B19) and type II (B8) IFN binding proteins are not required for virus replication in 37 cultured cells. Studies on immune responses in mice after DNA prime/NYVAC boost 38 revealed that deletion of B8R and B19R genes improved the magnitude and quality of 39 the HIV-1-specific CD8+ T cell adaptive immune responses, and impact on their 40 memory phase changing the contraction, the memory differentiation, the magnitude 41 and the functionality profile. For B cell responses, deletion of the viral genes B8R 42 and/or B19R has no effect on antibody levels to HIV-1 Env. These findings revealed 43 that single or double deletion of viral factors (B8 and B19) targeting the IFN pathway is 44 a useful approach in the design of improved poxvirus-based vaccines. 45