Poxvirus as a vector to transduce human dendritic cells for immunotherapy:abortive infection but reduced APC function

Dendritic cells (DC) are potent antigen-presenting cells (APC). Ongoing pre clinical and clinical studies exploit this capacity for the immunotherapy o f tumors. We tested vaccinia virus (VV) as a vector to transduce human DC. Immature and mature DC were prepared from blood monocytes and infected with (1) recombinant VV expressing GFP to analyze infection rates, virus replic ation in DC and the effect of infection on DC phenotype and (2) recombinant VV expressing beta-galactosidase (beta GAL) under the control of viral ear ly, intermediate and late promoters to analyze the poxvirus-driven gene exp ression. While the infection rate in DC was comparable to a permissive fibr oblast cell line, viral beta GAL gene expression was limited to early promo ters. Genes under the control of virus late promoters were not expressed by VV in DC, indicating an abortive infection. VV infection selectively reduc ed the surface expression of the costimulatory molecule CD80 and the DC mat uration marker CD83 on mature DC while other surface molecules including CD 86 and MHC remained unchanged. In line with this finding, there was a prono unced reduction in the capacity of VV-infected DC to stimulate allogeneic o r autologous T cells in mixed lymphocyte reactions. Furthermore, VV infecti on inhibited the maturation of immature DC after exposure to proinflammator y cytokines. These results indicate that VV-derived vectors may have comple x effects on their target cells. in the case of DC used for immunotherapy, this may be detrimental to their function as potent APC and particularly th eir capacity to activate T helper cells.