To confer adenovirus vectors (AdV), the feature of integration into the host cell genome hybrid vectors were characterized in vitro, which express vectors derived from the prototypic foamy virus (FV) in the backbone of a high-capacity AdV. FVs constitute a subfamily of retroviruses with a distinct replication pathway and no known pathogenicity. In the absence of envelope glycoprotein, the prototypic FV behaves like a retrotransposon, while it behaves like an exogenous retrovirus in its presence. Two principle types of vectors, which either allows the intracellular (HC-FAD-7) or, in addition, the extracellular (HC-FAD-2) pathway were constructed. In both chimeras the expression of the FV vector was controlled by the tetracycline-regulatable system. Hybrids were produced close to 10(10) infectious units/ml. By Southern blotting, the functionality of the hybrid vectors to generate host cell genomic integrants was shown. However, the efficiency of HC-FAD-7 to establish stable transgene expression was rather low, while around 70% of cells were stably transduced in secondary round following primary transduction with HC-FAD-2 at an MOI of 100. Given the benign characteristics of high-capacity adenovirus and FV vectors, hybrids based on HC-FAD-2 are probably suited for an in vivo application.