Recently, much attention has been paid to genetically recombinant viruses, including replication-incompetent virus vectors, which lack self-replicating ability and contain therapeutic genes, and conditionally replicating viruses, which show antitumor effects by specifically replicating only in tumor cells. The basic strategy for the development of replication incompetent vectors and conditionally replicating viruses is to enhance safety of the viruses as well as efficiencies of gene expression.
In this review, we mainly introduce recombinant adenoviruses (Ads) containing microRNA-regulated gene expression system. Expression of therapeutic genes in replication incompetent vectors and replication of conditionally replicating Ads were efficiently regulated in a cell-specific pattern by microRNA-regulated gene expression system, resulting in enhancement of safety of recombinant Ads.

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Nature has evolved adeno-associated viruses (AAVs) very slowly by natural selection in their long history. However, since over 100 AAV serotypes and variants were discovered in primates in 2002, their evolution has been significantly accelerated by human intervention. Their simplest structure and ease of genetic manipulation have allowed exploitation of rational design and directed evolution approaches to create AAVs with desired properties. It has become possible to create custom-made AAV vectors for various experimental and therapeutic purposes.

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Varicella-zoster virus (VZV) infection is a causative agent of varicella and zoster. Varicella vaccine has been developed to reduce the morbidity of varicella. The Oka vaccine is the only attenuated live varicella vaccine permitted for use by WHO.
Recently we have generated a recombinant virus expressing mumps virus (MuV) HN protein based on the varicella vaccine. The recombinant virus could induce neutralizing antibodies against both VZV and MuV in guinea pig, thus indicating that the virus may be a candidate for polyvalent live vaccine against MuV and VZV infection.
Here we have summarized about the Oka vaccine, the recombinant virus and the application for a polyvalent live vaccine of the recombinant virus.

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Live viruses are new strategies using biological agents to treat cancer. The oncolytic virotherapy is currently under preclinical and clinical investigation all over the world. Attenuated Edmonston B measles vaccine strain (MV-Edm) is nonpathogenic and is being used for vaccination. On the other hand, MV-Edm has potent antitumor activity against several human tumors. In the text, we have focus on elucidation and control of the infection step via binding to host receptors and fusion of MV-Edm by the use of molecular virology techniques. Based on our findings, oncolytic measles viruses have been genetically engineered to target tumor cells and then kill them.

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The baculovirus, Autographa californica nuclear polyhedrosis virus (AcNPV), is an insect virus and has been used as a vector for a high level expression of foreign proteins in insect cells. Furthermore, AcNPV has been shown to infect mammalian cells and express foreign genes under the control of the mammalian promoters. We have previously shown that intranasal inoculation of AcNPV induces a strong innate immune response and protects mice from a lethal challenge of influenza viruses. The activation of innate immunity was shown to closely link to the secondary adaptive immune responses of the host. Members of the Toll-like receptor (TLR) family are essential components in this process. The production of inflammatory cytokines was severely reduced in peritoneal macrophages (PEC) and dendritic cells (DC) derived from mice deficient in MyD88 or TLR9 after cultivation with AcNPV. In contrast, a significant amount of interferon (IFN)-α was still detectable in the PEC and DC of the mice after stimulation with AcNPV, suggesting that a TLR9/MyD88-independent signaling pathway might participate in the production of IFN-α by AcNPV. Recently, the cytoplasmic helicase proteins RIG-I and MDA5 have been identified as viral dsRNA detectors to facilitate type-I IFN production through the interaction with an adaptor molecule IPS-1. However, neither RIG-I, MDA5 or IPS-1 was required for the production of type-I IFN and inflammatory cytokine by AcNPV in PEC and DC. These results suggest that novel signaling pathway(s) other than TLR and IPS-1-dependent pathways may participate in the induction of type I IFN in immune competent cells in response to AcNPV infection.

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Recently established reverse genetics of influenza virus allows us to generate the recombinant viruses with arbitrarily modified viral proteins. The recombinant viruses are now utilized as useful tools in basic research fields. Moreover, in application, H5N1 pre-pandemic vaccines, which are now stockpiled in many countries, were generated by using the reverse genetics to attenuate the virus. In the future, the technology of reverse genetics will contribute us to develop the next generation of influenza vaccines. On the other hand, construction of the recombinant viruses that express foreign proteins, epitopes, or genes may lead to application for multivalent vaccines inducing effective immune responses and vectors for gene therapy. A variety of such approaches are now in underway to exploit recombinant viruses for practical use.

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