Background: Attenuated pox viruses such as Modified Vaccinia Ankara (MVA) have generated significant interest as vectors for HIV vaccines. However, many features of MVA’s interaction with the host immune system are poorly understood. In particular, the range of cellular targets within the immune system and the immediate effects of the infection on these cells have not been clearly delineated. Knowledge of these viral targets and effects will facilitate the design of rational pox virus-based HIV vaccine candidates.

Methods: Using recombinant MVA and Vaccinia Virus (VV) expressing GFP, we have determined the cellular tropism of MVA and VV in primary human PBMC and cultured antigen presenting cells, by both confocal microscopy and flow cytometry. To characterize infected cells, flow cytometric analyses for expression of viral gene products, cell surface phenotypic markers, and apoptosis were performed.

Results: In contrast to widespread beliefs, the tropism of MVA and VV is very limited for primary human targets. These viruses readily infect dendritic cells (DCs, both ex vivo- and in vivo-derived), an observation that has favorable implications for MVA as a vaccine vector. MVA and VV were also found to infect monocytes/macrophages, a smaller fraction of B-cells, and virtually no resting T-cells. Interestingly, activation of T-cells renders them highly susceptible to infection. MVA/VV-infected activated T-cells express gene products from both early and late stages of the virus life cycle. In contrast, infected DCs only express early viral genes, do not mature following infection, and die via apoptosis. These features of DC infection may thwart their direct antigen presenting capability, and engender speculation regarding the generation of cellular immune responses following MVA vaccination.

Conclusions: Our findings demonstrate that the range of cells susceptible to MVA/VV infection is highly restricted to key populations involved in the generation of immune responses, such as DCs, monocytes/macrophages, and activated T-cells (with variable B-cell infection). The described features of MVA and VV cellular tropism may influence early virus dissemination following primary infection and the generation of immune responses following vaccination with pox virus vectors. Importantly, this characterization of the consequences of infection on DCs suggests promising modifications to MVA-based HIV vaccines that should serve to enhance their immunogenic potential.