Biology and application of alphaviruses in gene therapy

Abstract

The broad host cell range and high expression levels of transgenes are features that have made alphaviruses attractive for gene expression studies and gene therapy applications. Particularly, Semliki Forest virus vectors have been applied for large-scale production of recombinant membrane proteins for drug screening purposes and structural biology studies. The high preference of expression in neuronal cells has led to many applications of alphavirus vectors in neuroscience. Studies on localization and transport of recombinant proteins as well as electrophysiological recording have become feasible in primary cultures of neurons and hippocampal slice cultures. Alphaviruses have frequently been used as vaccine vectors for expression of antigens against viruses and tumors. Administration of recombinant viral particles, DNA plasmids or in vitro transcribed RNA has resulted in protection against challenges against lethal viruses and tumors in rodent and primate models. Intratumoral injections of alphavirus vectors expressing reporter and immunostimulatory genes have led to significant tumor regression in mouse models. Modifications of the viral envelope structure have generated targeted Sindbis virus vectors. Astonishingly, conventional Sindbis vectors have demonstrated tumor-specific targeting in animal models due to the high density of laminin receptors on cancer cells. Moreover, encaspulation of Semliki Forest virus vectors in liposomes has provided a means of achieving tumor targeting and protection against the host immune response. Much attention has also been given to the engineering of novel mutant alphavirus vectors with properties such as reduced cytotoxicity, prolonged duration of transgene expression and improved survival of host cells.