Host Immune Response To Vaccinia

The immune response to vaccinia viral vectors serves as our paradoxical friend and foe in attempting to develop them into effective vectors for gene therapy. On the one hand, the vigorous immune response is desirable because we believe that it enhances its potential as a vaccine. On the other hand, the vigorous immune response leads to premature clearance of the virus before adequate levels of replication have occurred, thus decreasing the level of transgene expression and possibly the overall efficacy.

Most viruses that infect human cells are also endemic in the population; therefore, many patients will have circulating antibodies against the viruses and preformed cellular precursors. Vaccinia is unique in that it is not endemic to humans, and because widescale smallpox immunizations terminated in the 1970s, young patients will not have been exposed to the virus. Most cancer patients, however, are older and have been exposed to vaccinia. As with other virus vectors, however, reinfection is possible after prior exposure. Laboratory workers and military personnel who undergo revaccination for smallpox usually form pox vesicles in the skin, despite prior vaccination. This has also been demonstrated in tumor vaccine trials in patients previously immunized (60). Workers at vaccine production plants in the past suffered from repeated skin infections with vaccinia and pox lesions in the skin. Some viruses can avoid circulating antibodies by mutating their coat proteins and changing serotype. This is not seen with vaccinia virus. However, vaccinia has evolved expression of immuno-suppressive proteins (61). Viral surface proteins act as complement inhibitors, and the extracellular envelope is known to be almost completely resistant to antibody neutralization (62).

Both cellular immunity and neutralizing antibodies play a role in protection from vaccinia infection. The T cell response to vaccinia seems to be quite potent and is probably more important than antibodies in the primary host resistance to the virus. Progressive vaccinia correlates with a defect in cellmediated immunity (63). In murine models, in the absence of a functional T cell population vaccinia is able to replicate and express genes within tumor cells at high levels for greater than 30 days (64). In an immunocompetent host, the window of gene expression only lasts for about 8 days with high levels of gene activity lasting approximately 4 days (58).

The success of vaccinia as a gene therapy vector relies on its efficiency in vivo. Vaccinia has developed a wide range of immune evasion strategies in order to survive in vivo (Table 2). Understanding and manipulating these factors may optimize the vector for clinical use. If one examines these factors closely, it is clear that the majority of them encode for proteins that are able to actively suppress both innate immunity and the development T helper 1 (Th1) immune response. For example, vaccinia virus has adopted at least 3 different genes whose product can block the function of the interferon (IFN) family members IFN a/3,7 (65-67). These factors are secreted by a variety of cells in response to innate danger signals. They can induce an antiviral state and up-regulate adaptive immune functions. Vaccinia also carries genes for multiple inhibitors of chemokines, some of the earliest substances produced during the initiation of an immune response (68-70).

Vaccinia encodes for at least 3 factors that can directly block the function of IFN-7, one of the most potent Th1 cyto-kines (71-73). In addition, vaccinia encodes for the recently described IL-18-binding protein (IL-18BP) (74-76). IL-18BP is a naturally produced soluble factor that blocks the binding of IL-18 to its cognate receptor. IL-18BP has been shown to be one of the most potent inhibitors to the development of a Th1-biased immune response (77). Vaccinia virus also encodes for several other immunosuppressive factors, including factors to block complement activation, IL-13 soluble receptor, and soluble tumor necrosis factor receptor antagonist (78-81). These observations suggest that subverting the early innate immune response and slowing the development of Th1

Table 2 Vaccinia Gene Products that Inhibit Immune

Response

Table 2 Vaccinia Gene Products that Inhibit Immune

Response

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