Role of alpha(v) integrins in adenovirus cell entry and gene delivery

Adenoviruses (Ad) are a significant cause of acute infections in humans; ho wever, replication-defective forms of this virus are currently under invest igation for human gene therapy Approximately 20 to 25% of all the gene ther apy trials (phases I to III) conducted over the past 10 years involve the u se of Ad gene delivery for treatment inherited or acquired diseases. At pre sent, the most promising applications involve the use of Ad vectors to irra dicate certain nonmetastatic tumors and to promote angiogenesis in order to alleviate cardiovascular disease. While specific problems of using Ad vect ors remain to be overcome las is true for almost all viral and nonviral del ivery methods), a distinct advantage of Ad is the extensive knowledge of it s macromolecular structure, genome organization, sequence, and mode of repl ication. Moreover, significant information has also been acquired on the in teraction of Ad particles with distinct host cell receptors, events which s trongly affect virus tropism. This review provides an overview of the struc ture and function of Ad attachment (coxsackievirus and Ad receptor [CAR]) a nd internalization (alpha(nu) integrins) receptors and discusses their prec ise role in virus infection and gene delivery. Recent structure studies of integrin-Ad complexes by cryoelectron microscopy are also highlighted. Fina lly, unanswered questions arising from the current state of knowledge of Ad -receptor interactions are presented in the context of improving Ad vectors for future human gene therapy applications.