Viruses in therapy--royal road or dead end?

The idea of using viruses as gene vehicles to combat disease is tantalizing for the simplicity of its principle, and for the unlimited perspectives that it raises. Yet the initial enthusiasm gave way to deep skepticism, when the complex challenges became apparent. Issues that hampered clinical successes include the specificity and efficiency of gene delivery; the immune response to viral vectors and targeted cells; standardized and affordable production of vectors; and safety for patients and environment. More recently, some obstacles could be mastered through a better understanding of vector-cell-interactions, vector-induced pathogenesis and principles of vector engineering technologies. First clinical successes became apparent, giving raise to a second waive of effort to exploit viruses in gene therapy. Future challenges include the targeting of stem cells, through receptor tropism and the regulation of gene expression; controlled evasion of host defense; combining the beneficial features of several virus vectors; realistic animal models; and clinical protocols for standardized evaluation of safety and efficacy. Monogenetic disorders were initially regarded as principal targets for gene therapy. However, most clinical trials are now addressing cancer or HIV infection. Cancer gene therapy is aiming at the destruction of malignant cells, whereas 'conventional' gene therapy frequently establishes or restores a long-term function in target cells. Therefore, the requirements for viruses to be used against cancer are fundamentally different from conventional vectors. Host cell death, immune response, and spread of replicating viruses can all contribute to oncolytic efficacy. However, limiting these deleterious effects to tumor cells is mandatory for clinical safety. A number of approaches have been taken to improve the specificity and/or efficacy of cancer virotherapy. Recent studies concerning oncolytic adenoviruses exemplify these strategies.