Innate Immune Mechanisms Dominate Elimination of Adenoviral Vectors FollowingIn VivoAdministration

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Abstract
To evaluate the contribution of the innate immune component of host defense in clearing the genome of adenovirus (Ad) vectors following in vivo administration, the Ad vectors AdCMV.βgal (expressing β-galactosidase) or AdCMV.Null (expressing no gene) were administered intravenously to immunocompetent or immunodeficient mice, and the amount of vector genome was quantified in the liver. Strikingly, 90% of vector DNA was eliminated within 24 hr. There was no increase in vector DNA in other tissues over this period, suggesting that rapid clearance of vector genome resulted from local degradation. After 24 hr, vector elimination was slow, with only 9% of the initial amount of vector genome cleared over the subsequent 3 weeks. Importantly, early phase (0–24 hr) elimination of vector DNA was independent of the transgene and similar in immunocompetent and nude animals. These observations suggest two phases of Ad vector elimination: a previously recognized late, immune-related elimination, and the early, innate immune elimination described in the present study. The early phase of vector loss is, by far, the dominant mechanism, an observation that has implications in developing strategies to maintain persistent expression of the newly transferred gene following in vivo gene therapy. Adaptive, virus-specific immune responses are thought to be responsible for the lack of persistence of the newly transferred adenovirus (Ad) genome following in vivo administration. The present study demonstrates that innate immune mechanisms also contribute significantly for the loss of vector genome over time. Following intravenous administration, 90% of the vector genome was eliminated from mouse liver within the first 24 hr. This loss was independent of dose, transgene, and was also seen in immunodeficient animals. The subsequent loss of vector genome was much slower, demonstrating that the early phase of vector elimination is the dominant mechanism. Circumventing these innate immune processes might be helpful in developing strategies to prevent loss of vector genome and achieve persistent expression.