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Role of alpha(v) integrins in adenovirus cell entry and gene delivery
1Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA. gnemerow@scripps.edu
Abstract:
Adenoviruses (Ad) are a significant cause of acute infections in humans; however, replication-defective forms of this virus are currently under investigation for human gene therapy. Approximately 20 to 25% of all the gene therapy trials (phases I to III) conducted over the past 10 years involve the use of Ad gene delivery for treatment inherited or acquired diseases. At present, the most promising applications involve the use of Ad vectors to irradicate certain nonmetastatic tumors and to promote angiogenesis in order to alleviate cardiovascular disease. While specific problems of using Ad vectors remain to be overcome (as is true for almost all viral and nonviral delivery methods), a distinct advantage of Ad is the extensive knowledge of its macromolecular structure, genome organization, sequence, and mode of replication. Moreover, significant information has also been acquired on the interaction of Ad particles with distinct host cell receptors, events which strongly affect virus tropism. This review provides an overview of the structure and function of Ad attachment (coxsackievirus and Ad receptor [CAR]) and internalization (alpha(v) integrins) receptors and discusses their precise role in virus infection and gene delivery. Recent structure studies of integrin-Ad complexes by cryoelectron microscopy are also highlighted. Finally, 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.
Insights
Adenoviruses (Ad) are explored for gene therapy, leveraging their known structure and host cell interactions. Understanding Ad attachment and internalization receptors is key to improving Ad vectors for treating diseases.
Area of Science:
- Virology
- Gene Therapy
- Molecular Biology
Background:
- Adenoviruses (Ad) are common human pathogens, but replication-defective forms are investigated for gene therapy.
- Ad vectors are used in 20-25% of gene therapy trials for inherited and acquired diseases.
- Potential applications include cancer treatment and cardiovascular disease therapy.
Purpose of the Study:
- To review the structure and function of Adenovirus attachment and internalization receptors.
- To discuss the role of these receptors in Adenovirus infection and gene delivery.
- To highlight recent structural studies and identify future research directions for improving Adenovirus vectors.
Main Methods:
- Review of existing literature on Adenovirus structure, genome, replication, and host cell interactions.
- Analysis of studies on Adenovirus attachment (coxsackievirus and Ad receptor [CAR]) and internalization (alpha(v) integrins) receptors.
- Inclusion of recent cryoelectron microscopy studies on integrin-Adenovirus complexes.
Main Results:
- Adenoviruses utilize specific receptors, including CAR for attachment and alpha(v) integrins for internalization, which dictate virus tropism.
- Extensive knowledge of Adenovirus structure and replication facilitates vector development.
- Cryoelectron microscopy provides detailed insights into integrin-Adenovirus interactions.
Conclusions:
- Understanding Adenovirus-receptor interactions is crucial for optimizing Adenovirus vectors for gene therapy.
- Further research into these interactions can address current limitations and enhance vector efficacy.
- Targeting specific receptors holds promise for improving Adenovirus-mediated gene delivery in future therapeutic applications.