Efficient transduction of human monocyte-derived dendritic cells by chimpanzee-derived adenoviral vector.

Using recombinant adenoviruses (Ads) to target host dendritic cells (DCs) presents an attractive prospect for immunization. The efficacy of commonly used human Ad-derived gene transfer vectors for antigen delivery in humans is often compromised by preexisting anti-Ad immunity, acquired by the majority of human population as a result of frequent naturally occurring virus infections. As an alternative vector we propose chimpanzee-derived recombinant adenoviruses, which are poorly neutralized by human sera. In the present study we examine the ability of one such vector, AdC68, to transduce and activate human monocyte-derived DCs in culture. We found that AdC68 could efficiently transduce both immature and mature DCs at levels similar to those by the human serotype 5 Ad recombinant. Exposure of immature DCs to AdC68 did not alter the expression of activation and maturation marker molecules on the cell surface. Nevertheless, the transduction induced DCs to secrete interferon alpha and interleukin (IL)-6, but not IL-12 or tumor necrosis factor alpha. In addition, AdC68-transduced immature DCs could stimulate proliferation of autologous T lymphocytes. This is the first report describing a chimpanzee-derived recombinant Ad as a vector for transduction of human DCs.

Preexisting immunity to adenovirus in rhesus monkeys fails to prevent vector-induced toxicity.

In an earlier study we evaluated innate immune responses to a first-generation adenoviral vector infused into the portal vein of rhesus monkeys who had never been exposed to adenovirus previously. In these animals, the systemic administration of E1/E3-deleted adenoviral vectors resulted in immediate activation of innate immunity and serious toxicity caused by targeting of vector to antigen-presenting cells and systemic inflammation. We analyze here how these responses are affected by vector-specific preexisting immunity that was induced by intramuscular immunization 6 months prior to evaluation. Our results show that preexposure to the vector substantially diminishes the transgene expression in most tissues but has little effect on gene transfer. Significantly, preimmunization does not eliminate systemic vector-induced toxicity. These conclusions are based on the presence of clinical features of coagulopathy and elevated levels of proinflammatory cytokine interleukin-6 in the serum of animals treated with vector after intramuscular immunization. Furthermore, preexisting immunity appears to induce a vector-specific inhibitory effect on erythroid progenitor development in the bone marrow that is not found when naive animals are challenged with vector.