A44l

Steroid synthesis

responses is important for the efficacy of vaccinia therapy (69,82).

Other studies have confirmed the critical role of Th1 response to clearance of vaccinia viral infection. Van den Broek et al. examined the effect of Th1 (IFN-y, IL-12) and Th2 (IL-4, IL-10) balance in the clearance of vaccinia virus in mice using cytokine knockouts (KOs) (83). Vaccinia viral replication was enhanced in IL-12 and IFN-y KO mice, with IL-12-/-demonstrating greater susceptibility to infection than IFN-y-deficient mice. Interestingly, development of antivaccinia CTL was completely abrogated in IL-12 KO mice but remained normal in IFN-y-/-. In contrast, IL-4- and IL-10-defi-cient mice showed marked enhancement of vaccinia viral clearance, suggesting that these cytokines naturally suppress the host response to vaccinia. IL-10-/- mice exhibited greater inhibition of viral replication than IL-4-deficient mice. When the effects of each cytokine on vaccinia infection was examined in recombinant viral constructs, local expression of IL-4 showed a much greater inhibition of host responses. In fact, although the absence of IL-10 resulted in improved clearance of vaccinia virus that was mediated by increased levels of IL-6 and IL-1, the local expression of IL-10 had little to no effect on viral clearance. Similarly, Deonarain et al. showed that IFN alpha/beta KO mice demonstrate markedly enhanced susceptibility to vaccinia viral infection (84).

There are several strategies that have been investigated to circumvent the problem of premature immune clearance. First, one could create a virus that is less recognizable by the immune system. This could be accomplished by mutating the viral coat of the vaccinia virus to make it less cross-reactive with antibodies. However, the poxviridae and, in particular, vaccinia virus is antigenically very complex and it is unlikely that 1 or 2 mutations in viral envelope genes could significantly alter antibody recognition. Further, any mutations in the viral envelope may decrease the infectivity of the virus. Another strategy would be to develop other poxviruses that are able to selectively infect and lyse human tumor cells that do not cross-react with vaccinia. Viruses from the Yatapox genus infect monkeys and secondarily have infected monkey caretakers (85). These viruses do not cross-react with vaccinia, yet they cause human disease and replicate in human cells. The yabalike disease virus is under investigation as another replicating poxvirus for tumor-directed gene therapy (86). Avian poxviruses also do not cross-react with vaccinia virus and have become popular expression vectors (87). They do not replicate in human cells and are less efficient vectors overall.

Another approach to circumventing premature clearance of our vaccinia vector is to create a viral recombinant that actively suppresses host cellular immune responses. Several groups have reported that insertion of Th2-like cytokines such as IL-4 or IL-10 into vaccinia virus increases in vivo viral replication and slows host clearance of infection (83,88,89). However, creation of a virus that is not recognized by the immune system obviously creates serious safety concerns for the population as a whole because unforeseen events could lead to a pathogenic virus that is not immunologically cleared.

A third approach to improving in vivo viral replication involves reversible transient host immunosuppression. Because of the growth of knowledge in solid organ transplantation, we now have available multiple immunosuppressive agents that can very precisely target specific pathways of the host immune response. This knowledge, combined with our growing understanding of the immune response to vaccinia virus, should allow us to reversibly slow the immune response to our vector. This will theoretically allow for more efficient in vivo viral replication in the tumor, higher transgene expression, and greater oncolysis. This will be a feasible approach with vaccinia mutants exhibiting tumor selectivity.

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