Our work focuses on nonreplicating adenovirus vectors and their biodistribution and toxicity in vivo. After intravenous injection of adenoviral vectors, the majority of the vector is quickly phagocytosed by macrophages in the liver, and it has been widely assumed that adenovirus vectors are always hepatotropic. To study the effect of liver disease on the biodistribution of adenovirus vectors, we have studied the distribution of adenovirus vectors in two rat models of liver cirrhosis. Surprisingly, after intravenous injection into cirrhotic rats, adenovirus vectors are quickly taken up by intravascular macrophages in the lungs, with greatly reduced uptake by macrophages in the liver. This phenomenon of pulmonary reticuloendothelial uptake has previously been reported in numerous human cases using the radiocolloid tracer 99m-Tc sulfur colloid, particularly in cases of congenital or acquired liver disease. This suggests that a subset of patients are at risk for unexpected pulmonary uptake of adenovirus vectors after intravenous or intraarterial administration. We are currently following through to determine whether adenovirus vectors cause any pulmonary pathology in cirrhotic rats.
