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Since RNA virus genome encodes only a limited number of viral proteins, replication of RNA virus mostly relies on host cells. Elucidation of host proteins that play important roles in the virus replication cycles contributes not only to fundamental virology research but also to applied research such as development of antiviral drugs. We revealed that Ebola virus matrix protein VP40 utilized host COPII transport machinery for its intracellular transport to the plasma membrane. Second, we demonstrated that enterovirus A71 used Scavenger receptor class B member 2 (SCARB2) as a cellular receptor. Finally, we found that host protein CLUH played an important role in the subnuclear transport of influenza virus ribonucleoprotein (vRNP) complexes. Here, I would like to briefly introduce these findings.

Hepatitis C virus (HCV) infects over 170 million people worldwide and is a major cause of life-threatening liver diseases such as liver cirrhosis and hepatocellular carcinoma. In current research, we aimed to clarify the mechanism of hepatic tropism of HCV infection. Although non-hepatic cells could not permit replication of HCV RNA, exogenous expression of liver specific miRNA, miR-122 facilitated efficient replication of viral RNA through direct interaction with 5'UTR of viral genome, indicating that miR-122 is one of the key determinants for hepatic tropism of HCV infection. In spite of efficient replication of viral RNA, formation of infectious particles was not observed in non-hepatic cells exogenously expressing miR-122. We found that expression of apolipoprotein E (ApoE) facilitated the formation of infectious HCV particles in non-hepatic cells, indicating that not only miR-122 but also ApoE participate in tissue tropism of HCV infection. To understand the exact roles of miR-122 and apolipoproteins in hepatic tropism of HCV, we established miR-122 and ApoB/ApoE knockout (KO) Huh7 cells, respectively. Although slight increase of intracellular HCV RNA and infectious titers in the culture supernatants was observed, propagation of HCV was impaired in miR-122 KO Huh7 cells. After serial passages of HCV in miR-122 KO cells, we obtained an adaptive mutant that possessed G28A substitutions in the 5'UTR of the HCV genome and exhibited efficient translation and replication in both miR-122 KO Huh7 and non-hepatic cells without exogenous expression of miR-122. These results suggest that HCV mutants replicating in non-hepatic cells in an miR-122-independent manner participate in the induction of extrahepatic manifestations in chronic hepatitis C patients. Deficiency of both ApoB and ApoE strongly inhibited the formation of infectious HCV particles. Interestingly, expression not only of ApoE but also of ApoA or ApoC could rescue the production of infectious HCV particles in ApoB/ApoE KO cells, suggesting that exchangeable apolipoproteins redundantly participate in the formation of infectious HCV particles.

Plants defend themselves from virus infection by RNA silencing and resistance (R) gene-mediated mechanisms. Many dominant R genes encode nucleotide-binding site and leucine-rich repeat (NB-LRR)-containing proteins. NB-LRR proteins are also encoded by R genes against bacteria or fungi, suggesting a similar mechanism underlies defense systems to diverse pathogens. In contrast, several non-NB-LRR-type R genes have recently been cloned, each of which differs from others in sequences and functions. In this review, we introduce a diversity of R gene-mediated plant defense systems against viruses. Tm-1, JAX1, and Scmv1, resistance genes against tomato mosaic virus, potexviruses, and sugarcane mosaic virus, respectively, inhibit virus multiplication at a single cell level. The RTM1, RTM2, RTM3 genes of Arabidopsis thaliana inhibit systemic transport of potyviruses through the phloem. STV11 of rice against rice stripe virus and Ty-1 and Ty-3 genes of tomato against tomato yellow leaf curl virus allow low level virus multiplication and confer tolerance. The wide diversity of plant defense systems against viruses implies their recent emergence. We suggest that plants evolved new defense systems to counter infection by viruses that had overcome pre-existing defense systems (RNA silencing and NB-LRR-type R gene-mediated systems).

Arenavirus is a genetic term for viruses belonging to the family Arenaviridae and is presented from lymphocytic choriomeningitis virus (LCMV), which shows almost no pathogenicity to humans, to Lassa virus, Junin virus, Machupo virus, Chapare virus, Lujo virus, Sabia virus, and Guanarito virus, which shows high pathogenicity to humans. These viruses except for LCMV are risk group 4 pathogens specified by World Health Organization. Based on this designation, it is designated as Class I pathogens in Japan. Although there have been no reports excluding one imported case of the Lassa fever patient, it is not surprising whenever imported cases occur in our country. Considering the disease severity and mortality rate, it is an urgent matter to develop vaccines and therapeutic drugs in endemic areas, and maintenances of these are also important in countries other than endemic areas. However, basic research on highly pathogenic arenavirus infections and development of therapeutic drugs are not easily progressed, because handling in highly safe research facilities is indispensable. In this article, we will outline the current knowledge from the recent basic research on arenavirus to the development situation of antivirals against arenaviruses.

Zika virus (ZIKV) is one of the members of the Spondweni serocomplex within the genus Flavivirus of the family Flaviviridae. The virus was first isolated from a serum specimen from a sentinel non-human primate in the Zika forest of Uganda in 1947. ZIKV is transmitted by Aedes aegypti and A. albopictus in an urban cycle and maintained in a sylvatic cycle between Aedes mosquitoes and monkeys in Africa and Asia. Initially, the virus was thought to cause only mild and nonspecific clinical symptoms in humans. However, ZIKV became a serious public health concern in recent years due to an association with congenital malformation known as microcephaly in newborns as well as Guillain-Barré syndrome and other neurologic disorders in adults. The severe nature of complications of ZIKV infection have led to an urgent need for a safe and effective vaccine worldwide including Japan. The first large outbreak of disease caused by ZIKV infection was reported from the island of Yap, Micronesia in 2007. It was followed by outbreaks in French Polynesia, Cook Islands, Ester Island, and New Caledonia in 2013 and 2014. In 2015, ZIKV outbreak was reported in Brazil and has spread across the Latin America, and the Caribbean. The exact prevalence of ZIKV infection has not been reported because of the absence of a standardized protocol for differential diagnosis and its clinical resemblance to dengue virus and other flavivirus infections. In Japan, the first human case of ZIK fever, who developed illness soon after returning from French Polynesia, was reported in 2013, and until 2017, 20 imported cases were documented. Currently, research on ZIKV has progressed remarkably thus this article aims to review recent progress in virology, epidemiology, and pathology of ZIKV infection.

Herpes zoster, or shingles, results from the reactivation of latent varicella- zoster virus (VZV) in the dorsal-root or cranial-nerve ganglia, usually decades after primary infection. Herpes zoster is characterized by a vesicular rash with a unilateral and dermatomal distribution and is almost always accompanied by pain. Herpes zoster is not only skin disease, but also sometimes affects other organs, including central nerve system, eye, and facial nerve. The most common complications, such as postherpetic neuralgia (PHN), are more frequent, severe and impair patients' quality of life. For more than 10 years, in US, EU, and Australia, a live-attenuated vaccine against herpes zoster (Zostavax) containing the Oka VZV strain is licensed for use in adults who are 50 years of age or older. In Japan, a live attenuated varicella vaccine is also licensed for preventing herpes zoster in 2016. Two large randomized multinational efficacy trials (ZOE-50 and ZOE-70) showed that the novel herpes zoster subunit vaccine (shinglix) candidate containing varicella-zoster virus glycoprotein E (gE) and the AS01B adjuvant system reduced the risk of herpes zoster and PHN by more than 90%. This article aimed to review the epidemiology, pathophysiology and complications of herpes zoster and mention the efficacies and problems of the live-attenuated and the new recombinant herpes zoster vaccines.

Many tick-borne flaviviruses causes fatal encephalitis in humans and animals with severe sequelae. However, it remains unclear how viral replication and pathogenicity contribute to the neurologic manifestations. In this paper, I summarized the specific replication mechanism of tick-borne flaviviruses in neurons and their effect on the pathogenicity of neurological disease. Our findings of the unique virus-host interaction in central nerve system will improve further understanding of the molecular mechanisms of viral replication and the pathogenicity of neurotropic viruses.

Seven years have passed since the discovery of a novel infectious disease, severe fever with thrombocytopenia syndrome (SFTS) caused by a novel Phlebovirus, SFTS virus (SFTSV), in PR China. It was also confirmed that SFTS was endemic to Japan through an identification of a woman, who died of SFTSV infection in Yamaguchi prefecture in late 2012. Approximately 6 years have passed since the discovery of SFTS-endemicity in Japan. At present, SFTS is endemic to PR China, South Korea and western Japan. SFTSV is maintained between several species of ticks such as Haemaphysalis longicornis and wild and domestic animals in nature. Therefore, we cannot escape from the risk of being infected with SFTSV. Based on the similarity in the characteristics of the clinical symptoms including the high case fatality rate, mode of infection to humans, pathology and virology between SFTS and Crimean-Congo hemorrhagic fever (CCHF), SFTS should be classified as viral hemorrhagic fever. Although the time from the discovery of SFTS is still short, there have been many scientific reports on the epidemiological, clinical, and/or pathological, and virological studies on SFTS. Favipiravir was reported to show an efficacy in the prevention and treatment of SFTSV infections in an animal model. A clinical study to evaluate the efficacy of favipiravir in the treatment of SFTS patients has been initiated in Japan. Specific and effective treatment with antiviral drugs for and preventive measures of SFTS with vaccination shoued be developed through scientific, clinical, and basic research.

Polyomavirus (Py) is a non-enveloped, double stranded DNA virus that causes a myriad of devastating human diseases for immunocompromised individuals. To cause infection, Py binds to its receptors on the plasma membrane, is endocytosed, and sorts to the endoplasmic reticulum (ER). From here, Py penetrates the ER membrane to reach the cytosol. Ensuing nuclear entry enables the virus to cause infection. How Py penetrates the ER membrane to access the cytosol is a decisive infection step that is enigmatic. In this review, I highlight the mechanisms by which host cell functions facilitate Py translocation across the ER membrane into the cytosol.