By Dr Tomislav Meštrović, MD, PhD
Viruses have evolved by borrowing and modifying cellular genes to become extremely efficient at nucleic acid delivery to different cell types, avoiding at the same time immunosurveillance by an infected host. Those are the main properties that make viruses highly attractive gene-delivery vehicles (or vectors).
A proof of concept of viral gene therapy has been demonstrated by a large number of animal studies. Many types of viral vectors have been used in a wide array of basic and clinical studies, and genetic tools made possible to construct novel viruses intended for gene therapy, but also the development of vaccines.
Viral vectors can be applied in gene therapy in order to treat different diseases such as cancer, metabolic diseases, heart defects and neurodegenerative disorders. Vectors have been engineered based on adenoviruses, adeno-associated viruses, herpes simplex viruses, alphaviruses, lentiviruses and retroviruses.
Alternatively, chimeric viral-vector systems that combine advantageous properties of two or more viral systems are also being explored. One example is the poxviral/retroviral chimeric construct that allows cytoplasmic production of transducing defective retroviral particles.
Recent discovery that specific serotypes of adeno-associated virus gene delivery vectors have the ability to cross the blood-brain barrier upon intravenous administration has led to the possibility of perinatal gene therapy. This approach is becoming essential in treating diseases that manifest during the neonatal stage (or even in utero).
Most viral vectors are usually injected in blood, tumors or muscle tissue, but adenoviral and adeno-associated vectors can also be delivered via inhalation. Delivery procedures and availability of target cells upon delivery are important decision factors that significantly influence the spread of vector particles.
The choice of the appropriate viral vector for a specific gene transfer application necessitates careful consideration of several parameters – including stability constraints and production processes, the need for either transient or long-term expression, as well as the regulation of transgene expression.
Albeit viral-mediated gene delivery has shown to be the most effective way of gene transfer, non-viral means are also increasingly researched. A plethora of such non-viral systems incorporate parts of viral vectors in order to escalate the efficiency of gene delivery or expression.
Application of viral vectors in vaccinology
A growing level of information supports recombinant viral vector usage as a means of vaccination. Studies have demonstrated that, when antigen-expressing viral vectors are used, the elicited T- and B-cell responses are both wider and of a greater order of magnitude than after DNA immunization alone.
The underlying mechanism is in the replicative nature of the viruses – the vectors replicate inside the desired cell, mimic an authentic viral infection and result in the stimulation of innate anti-viral reactions in the antigen-expressing cell. A myriad of viral vaccine vectors can also induce apoptosis in the target cell.
Viral vector systems that have been studied the most extensively in vaccinology are adenovirus vectors and poxvirus vectors. Recombinant viral vectors have also been used to deliver human immunodeficiency virus (HIV) gene products, in conjunction with a protein boost using env-gp120 when searching for HIV vaccine, but results have been largely disappointing.
Last Updated: Oct 29, 2015