INNATE IMMUNE-MECHANISMS DOMINATE ELIMINATION OF ADENOVIRAL VECTORS FOLLOWING IN-VIVO ADMINISTRATION

To evaluate the contribution of the innate immune component of host de fense in clearing the genome of adenovirus (Ad) vectors following in v ivo administration, the Ad vectors AdCMV.beta gal (expressing beta-gal actosidase) or AdCMV.Null (expressing no gene) were administered intra venously 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 i n other tissues over this period, suggesting that rapid clearance of v ector genome resulted from local degradation, After 24 hr, vector elim ination 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 simil ar 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 describ ed in the present study, The early phase of vector loss is, by far, th e dominant mechanism, an observation that has implications in developi ng strategies to maintain persistent expression of the newly transferr ed gene following in vivo gene therapy.