Activiteiten per jaar
Lentiviral vectors are promising vaccine vector candidates, which have been extensively tested in pre-clinical models of infectious disease and cancer immunotherapy. They are also used in gene therapy clinical trials, both for the ex vivo modification of cells and for direct in vivo injection. It is therefore critical to understand the mechanism(s) by which such vectors might stimulate the immune system. We evaluated the effect of lentiviral vectors on myeloid dendritic cells (DC), the main target of lentiviral transduction following subcutaneous immunisation. Activation of DC cultures was independent of the lentiviral pseudotype, but dependent on cell entry and reverse transcription. In vivo transduced DC also displayed a mature phenotype, produced TNF-alpha, and stimulated naive CD8+ T cells. Lentiviral activation of DC was TLR-dependent as it was inhibited in TRIF/MyD88 knock out (-/-) DC. TLR3-/- or TLR7-/- DC were less activated, and reverse transcription was important for activation of TLR7-/- DC. Moreover, lentivirally transduced DC lacking TLR3 or TLR7 had an impaired capacity to induce antigen-specific CD8+ T cell responses. In conclusion, we demonstrated TLR-dependent DC activation by lentiviral vectors, explaining their immunogenicity. These data allow the rational development of strategies to manipulate the host's immune response to the transgene.
|Tijdschrift||Journal of Virology|
|Status||Published - 1 jun 2010|