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The distribution pattern of host proteases and their cleavage specificity for viral fusion glycoproteins are key determinants for viral tissue tropism and pathogenicity. The discovery of this protease-dependent virus tropism and pathogenicity has been triggered by the leading studies of the host-induced or -controlled modification of viruses by Homma et al. in 1970s. With the introduction of advanced protein analysis method, the observations by Homma et al. have been clearly explained by the cleavage activation of viral fusion glycoproteins by proteases. The molecular biological features of viruses, which show distinct protease specificity or dependency, have been also revealed by newly introduced nucleotide and molecular analysis method. Highly pathogenic avian influenza viruses (HPAIVs) have multi-basic cleavage motif in the hemagglutinin (HA) protein and are activated proteolytically by furin. Furin is ubiquitously expressed in eukaryotic cells and thereby HPAIVs have the potential to cause a systemic infection in infected animals. On the other hand, the HA cleavage site of low pathogenic avian influenza viruses (LPAIVs) and seasonal human influenza viruses is mono-basic and thus not recognized by furin. They are likely cleaved by protease(s) localized in specific organs or tissues. However, the protease(s), which cleaves mono-basic HA in vivo, has long been undetermined, although many proteases have been shown as candidates. Finally, recent studies using gene knocked out mice revealed that TMPRSS2, a member of type II transmembrane serine proteases, is responsible for the cleavage of influenza viruses with a mono-basic HA in vivo. A subsequent study further demonstrated that TMPRSS2 contributes to replication and pathology of emerging SARS- and MERS coronaviruses in vivo.

Herpes simplex virus (HSV) is one of the most extensively studied members of the family Herpesviridae and causes various human mucocutaneous diseases, such as herpes labialis, genital herpes, herpes whitlow, and keratitis. HSV also causes herpes simplex encephalitis, which can be lethal or result in severe neurological conditions in a significant fractions of cases, even with anti-viral therapy. Thus, despite the development of several anti-herpetic drugs, numerous substantial unmet medical needs exist with regards to HSV infections. Furthermore, genital herpes infections increase the likelihood of HIV infections and its transmission by 2- to 4-fold. This review discusses recent advances in basic research on HSV, primarily focusing on our recent studies, and the implications of our findings for the development of novel therapeutic and prophylactic agents for HSV infections.

An entirely plasmid-based reverse genetics system for animal rotavirus was established very recently. We improved the reverse genetics system to generate recombinant rotavirus by transfecting only 11 T7 plasmids for its 11 genes under the condition of increasing the ratio (3- or 5-fold) of the cDNA plasmids for NSP2 and NSP5 genes (11-plasmid system). Utilizing this highly efficient system, we engineered the first infectious recombinant rotaviruses harboring fluorescent (EGFP and mCherry) protein genes. In addition to these recombinant animal viruses, the first infectious recombinant human rotavirus (strain KU (G1P[8])) was also generated with the 11-plasmid system with some modifications. The availability of recombinant human rotaviruses will provide a genetic platform for a better understanding of the replication, pathogenicity, and other biological characteristics of this medically important virus and enable the rational development of next-generation human rotavirus vaccines.

Bombyx mori latent virus (BmLV) is a positive, single-stranded insect RNA virus with a close relationship to plant tymoviruses and currently classified as an "unclassified" tymovirus. BmLV is accumulated at extremely high levels only in cell lines derived from the silkworm, Bombyx mori, but it does not lead to lethality and establishes persistent infections. It was unknown whether BmLV affects the Baculovirus Expression Vector System using Bombyx mori nucleopolyhedrovirus, and how BmLV replicates and establishes persistent infections in insect cell lines. In this review, I introduce the discovery of BmLV, the establishment of virus-free cultured cells and the safety aspect of this virus. I also describe that two distinct small RNA-mediated pathways maintain the virus level in BmLV-infected cells, thereby allowing the virus to establish persistent infection. Virus-derived small interfering RNAs (vsiRNAs) and PIWI-interacting RNAs (vpiRNAs) are both produced as the BmLV infection progressed. We revealed that while siRNA pathway functions in both acute and persistent infection of BmLV, piRNA pathway functions only in the persistent infection of this virus.

Epstein-Barr virus (EBV) is a double stranded DNA virus of the family Herpesviridae. EBV is associated with a variety of lymphomas, and the mechanisms by which it promotes lymphomagenesis have been elucidated; this includes, for example, by translocation/activation of Myc in Burkitt lymphoma. However, the mechanisms by which it induces lymphoid tumors other than Burkitt lymphoma are unclear. Recently, we reported that the genome of EBV present in EBV-associated lymphomas harbors frequent intragenic deletions and that the deletion of a gene essential for virus replication promotes lymphomagenesis in a mouse model. Although intragenic deletions have been detected in other tumor viruses, little is known about the effects and importance of those of EBV, a large DNA virus whose genome encodes more than 70 genes. In this review, we summarize the role of EBV in lymphomagenesis with a focus on the impact of intragenic deletions.

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that infects T lymphocytes. HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an intractable neurodegenerative disease caused by HTLV-1 infection just like adult T cell leukemia/lymphoma (ATL) is, developing in a fraction of infected individuals. Here, we review the update information about the new drug development and therapeutic algorithm of HAM/TSP based on the resent research achievement in molecular pathogenesis and biomarkers.

The Baculoviridae is a large family of pathogens that mainly infects lepidopteran insects. Baculoviruseshave a large circular, supercoiled, and double-stranded DNA genome ranging from 80 to 180 kbp. Baculoviruses have been used as bioinsecticides as well as expression vectors for foreign genes, called Baculovirus Expression Vector System (BEVS). In addition to such industrial use, basic researches on baculoviruses such as genome sequencing and gene knockout have progressed rapidly. Functional characterization of baculoviral genes revealed that some of the non-essential auxiliary genes encode proteins controlling behavior, cell death, and molting in host insects. In this review, I describe our research progress on functional analyses of baculoviral genes that are involved in host manipulation.