C E3 Restored Vectors

The E3 region encodes genes that repress host response to infection through both reducing antigen presentation on the cell surface and protecting infected cells against tumor necrosis factor-a (TNF-a) and/or fas/fasL-mediated apoptosis. E3 is deleted in most adenovirus vectors to make room for the transgene within the length constraints of packaging. Arguing that E3 expression might increase persistence of vectors, several groups have sought to restore one or more E3 function. In mice, expression of the E3gp19K protein has been shown to reduce MHC class I expression in vitro (98) and cytotoxic T lymphocyte levels in vivo (99), but there are contradictory results on whether this translates into prolonged persistence (98,100). However, two studies have shown that the whole E3 region does in fact prolong vector persistence in vivo. This is true whether the E3 region is expressed from an exogenous promoter in the E1 region (101) or expressed from its own promoter in the normal position (102). Because E1 function is required for E3 expression, the latter result is surprising and may indicate that a low level of E3 expression is sufficient to prolong persistence. As with other modifications of the viral backbone, the critical question is if the expression of E3+ vectors would be longer in humans when administered in the route intended for therapy. This has not yet been answered.

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