Chapter 4 - Viral Vectors for Delivery of Antiviral Sequences

Abstract

As nucleic acid parasites, viruses have evolved efficient mechanisms for the delivery of DNA and RNA to cells. This feature has been exploited to develop recombinant viruses as vectors for various gene therapy-based treatments of viral infections. The generic approach to producing recombinant viral vectors entails separation of the engineered transgene from sequences encoding structural, enzymatic, regulatory, and accessory proteins. Typically, the transgene is coupled to the packaging signal whereas the other components required to generate the intact recombinant virions are provided in trans. Introducing all of the necessary constituents into packaging cells is then used to produce recombinant replication-defective vectors. To address concerns about toxicity and improve vectors' efficiency, several interesting approaches have been used to diminish interaction of viral vectors with host proteins and to alter vector tropism. To date, the main types of viral vectors used for antiviral gene therapy have been derived from adeno-associated viruses (AAVs), adenoviruses (Ads), and lentiviruses. AAVs are safe and efficient, but they are incapable of accommodating large antiviral cassettes. By contrast, Ads, particularly helper-dependent Ads, may deliver large cassettes to target cells. However, the toxicity of Ads, consequent to their powerful immunostimulation, is severely limiting. Lentiviruses, derived from human immunodeficiency virus-1, stably transduce cells and have broad tropism. The stable integration of lentivirus-derived proviral sequences into host cells is useful to achieve durable transgene expression, but insertional mutagenesis remains potentially problematic. Although currently available recombinant vectors are efficient, their propagation is very demanding of resources. Together with concerns about safety, this may limit widespread use of recombinant viral vectors for the treatment of globally common viral infections.