Membrane-associated RING-CH 8 (MARCH8) is one of 11 members of the recently discovered MARCH family of RING-finger E3 ubiquitin ligases. MARCH8 downregulates several host transmembrane proteins; however, its physiological roles remain unknown. Here we identify MARCH8 as a novel antiviral factor. The overexpression of MARCH8 in virus producing cells did not affect levels of lentivirus production, but markedly reduced viral infectivity. MARCH8 blocked the incorporation of HIV-1 envelope glycoprotein into virions by downregulating it from the cell surface, probably through their interaction, resulting in reduced viral entry efficiency. The inhibitory effect of MARCH8 on vesicular stomatitis virus G-glycoprotein was even more remarkable, suggesting a broad-spectrum inhibition of enveloped viruses by MARCH8. Importantly, the endogenous expression of MARCH8 was high in monocyte-derived macrophages and dendritic cells, and MARCH8 depletion in macrophages significantly increased the infectivity of virions produced from these cells. Our findings thus indicate that MARCH8, which is highly expressed in terminally differentiated myeloid cells, is a potent antiviral host transmembrane protein that reduces virion incorporation of viral envelope glycoproteins.
Viruses hijack host machineries for replicating themselves efficiently. Host protein quality control machineries (QC) not only assist protein folding to form bona fide proteins with active functions but also get rid of un/misfolded proteins via degradation to maintain the protein homeostasis. Previous studies have reported that viruses utilize QC at various steps for their lifecycles. Recently we defined Hsp70s and their cochaperones, DnaJs functions on Dengue lifecycle. Here we summarize the significance of QC on Dengue virus.
The H5N1 subtype is a highly pathogenic avian influenza virus currently circulating in birds in parts of Asia and northeast Africa, which has caused fatal human infections since 1997. Continuous circulation of the virus in endemic areas has allowed genetically diverse viruses to emerge, increasing the risk of H5N1 human infection. Although human infections with H5N1 have to date been limited, experimental evidence of the aerosol transmission of mutated viruses in a mammalian infection model has revealed the pandemic potential of H5N1 virus. One of the most important viral factors for host-adaptation of influenza virus is hemagglutinin (HA), which is the principal antigen on the viral surface and is responsible for viral binding to host receptors as well as endosomal membrane fusion. Our recent reports suggest that a fine balance of the HA properties, including receptor binding specificity and pH stability, is crucial for replication in human respiratory epithelia. This review provides an overview of current knowledge on the host-adaptive mechanism of H5N1 virus HA.
Most of the reported dominant disease-resistance genes in plants, R genes, encode NB-LRR immune receptors. Plant genomes carry many NB-LRR type R genes that recognize specific pathogens and induce resistance against them. Thus, this immune system in plants is thought to perform similar functions as the adaptive immune system in animals. In this review, we provide an overview of the resistance mechanisms, evolution, and agricultural applications of R genes against plant viruses. We also introduce recent advances in research into the regulatory mechanisms of R gene expression, focusing on regulation by microRNAs and introns. One of the most intriguing phenomena that occur following R gene-mediated recognition of viruses is programmed cell death around the initial infection site, although its significance in the survival strategies of plants remains to be elucidated. We discuss the possible benefits for plants of inducing such programmed cell death based on our empirical observations and some hypotheses from an ecological point of view.
Linear double-stranded RNAs (dsRNAs) of about 15 kbp in length are often found from healthy plants, such as bell pepper and rice plants. Nucleotide sequencing and phylogenetic analyses reveal that these dsRNAs are not transcribed from host genomic DNAs, encode a single long open reading frame (ORF) with a viral RNA-dependent RNA polymerase domain, and contain a site-specific nick in the 5' region of their coding strands. Consequently the International Committee on Taxonomy of Viruses has approved that these dsRNAs are viruses forming a distinct taxon, the family Endornaviridae the genus Endornavirus. Endornaviruses have common properties that differ from those of conventional viruses: they have no obvious effect on the phenotype of their host plants, and they are efficiently transmitted to the next generation via both pollen and ova, but their horizontal transfer to other plants has never been proven. Conventional single-stranded RNA viruses, such as cucumber mosaic virus, propagate hugely and systemically in host plants to sometime kill their hosts eventually and transmit horizontally (infect to other plants). In contrast, copy numbers of endornaviruses are low and constant (about 100 copies/cell), and they symbiotically propagate with host plants and transmit vertically. Therefore, endornaviruses are unique plant viruses with symbiotic properties.
We have found a novel mycovirus, MoCV1 in the rice blast fungus, Magnaporthe oryzae. MoCV1 has five dRNA segments as genome, and belong to Chrysoviridae tentatively. Using micro-spin column method or one-step reverse-transcription PCR (RT-PCR) assay, we detected a MoCV1-related virus from M. oryzae in Japan, whose sequence shares considerable identity with that of the MoCV1 Vietnamese isolate. To establish a system for comprehensive survey of MoCV1 infection in the field, we developed a reverse-transcription loop-mediated isothermal amplification (RT-LAMP) assay for direct detection of the virus. In this review, we introduce our current knowledges of MoCV1 properties for biochemical and molecular genetic aspects and also describe its negative effects to host fungus, which imply potentiality to utilize MoCV1 as bio-controller. Heterologous gene-expression system in yeast is employed to investigate biological activities or functions of mycoviral proteins in fungal host cells. MoCV1-A infection caused hypovirulence to the host fungus, unexpectedly, also resulted in the change of pathogenic races in several differential rice lines, namely S (compatible) to R (incompatible) reaction or R to S. The cause of epigenetic alteration is also discussed.
In this review, I made the phylodynamic comparisons of three plant viruses, Turnip mosaic virus (TuMV), Cauliflower mosaic virus (CaMV) and Cucumber mosaic virus (CMV), using the genomic sequences of a large numbers of isolates collected worldwide. We analyzed these genomic nucleotide sequences, in combination with published sequences, to estimate the timescale and rate of evolution of the individual genes of TuMV, CaMV and CMV. The main hosts of the viruses are Brassicaceae crops. We also compared these estimates from complete sequences with those from which non-synonymous and invariate codons had been removed. Our analyses provided a preliminary definition of the present geographical structure of three plant virus populations in the world, and showed that the time of migration of three plant viruses correlate well with agriculture history and human immigration.
Chronic infection with hepatitis C virus (HCV) is a global public health burden. It has been only several decades since this virus was first identified. In the meantime, a lot of progress has been made in the fight against HCV. Although the development of pegylated interferon (PEG-IFN) and its combination with ribavirin (RBV) has significantly increased effectiveness of IFN-based treatment, candidate patients must be assessed for eligibility prior to the treatment due to side effects of the regimens and the rates of sustained virological response (SVR) were only around 50%. In 2011, the protease inhibitor (PI) Telaprevir was firstly approved as a direct-acting antiviral (DAA) for hepatitis C. The second generation of PIs was subsequently introduced and, by adding PI to Peg-IFN/RBV, the SVR rates were found to be raised to up to 80%. Further, with the recent approval of the NS5A inhibitors and the NS5B polymerase inhibitors and with the SVR rates reaching 90% or greater using IFN-free, DAA combination regimens, it is now expected that the majority of patients with chronic hepatitis C can be cured of infection in the near future.
Chronic hepatitis C virus (HCV) infection is a major threat to global public health, because it is significantly correlated with the development of severe liver diseases including cirrhosis and hepatocellular carcinomas. Host molecules as well as viral factors are promising targets for anti-HCV preventive and therapeutic strategies. Multiple host factors such as CD81, SRBI, claudin-1, and occludin are involved in HCV entry into hepatocytes. In this paper, I first introduce our anti-HCV strategy targeting for host tight junction protein claudin-1. And this review also summarizes developments of other entry inhibitors to prevent initiation of HCV infection and spread. Entry inhibitors might be useful in blocking primary infections, such those as after liver transplantation, and in combination therapies with other anti-HCV agents such as direct-acting antivirals.
Hepatitis C virus (HCV) infects more than 170 million people in the world and chronic HCV infection develops into cirrhosis and hepatocellular carcinoma (HCC). Recently, the effective compounds have been approved for HCV treatment, the protease inhibitor and polymerase inhibitor (direct acting antivirals; DAA). DAA-based therapy enabled to cure from HCV infection. However, development of new drug and vaccine is still required because of the generation of HCV escape mutants from DAA, development of HCC after treatment of DAA, and the high cost of DAA. In order to develop new anti-HCV drug and vaccine, animal infection model of HCV is essential. In this manuscript, we would like to introduce the history and the current status of the development of HCV animal infection model.
Hepatitis C virus (HCV) infection often causes intrahepatic diseases, such as chronic hepatitis, liver chirrohsis, and hepatocellular carcinoma (HCC). Moreover, HCV infection exhibits various extrahepatic manifestations, such as thyroiditis, glucose and lipid metabolic disorder, and iron metabolic disorder. HCV infection is often associated with type 2 diabetes, involving hepatic fibrosis and poor prognosis. Type 2 diabetes increases the risk of HCC. We have been investigating molecular mechanisms of HCV-induced glucose metabolic disorder and we reported that HCV infection promotes hepatic gluconeogenesis through forkhead box O1 (FoxO1)-dependent pathway and that HCV infection suppresses the cell surface expression of glucose transporter 2 (GLUT2), resulting in suppression of glucose uptake. We have found that HCV NS5A protein plays important roles in these two independent pathways. Here we discuss the roles of HCV NS5A in HCV-induced glucose metabolic disorder.
Although chronic infection of hepatitis C virus (HCV) induces disorders of lipid metabolism, HCV is known to utilize lipid metabolism for efficient propagation in the liver. Due to the morphological and physiological similarities of HCV particles to lipoproteins, lipid-associated HCV particles are named lipoviroparticles. Previous reports have shown that lipoprotein receptors or cholesterol transporter participate in the entry of lipoviroparticles. In addition, recent analyses revealed that exchangeable apolipoproteins directly interact with the viral membrane to generate infectious HCV particles. In this review, we would like to discuss about involvement of lipoprotein and apolipoprotein in HCV lifecycle.
microRNA-122 (miR-122) is an abundant, liver-specific miRNA that regulates gene expression post-transcriptionally, typically by binding to the 3' untranslated region (UTR) of mRNAs, repressing their translation and mediating their degradation. Hepatitis C virus (HCV) is uniquely dependent on miR-122. Similar to conventional miRNA action, miR-122 recruits Argonaute-2 (AGO2) protein to the 5' UTR of the viral genome. However, in contrast to typical miRNA function, this stabilizes HCV RNA and slows its decay in infected cells. We found that HCV RNA is degraded primarily by the cytoplasmic 5' exonuclease XRN1 and that miR-122 acts to protect the viral RNA from XRN1-mediated 5' exonucleolytic decay. However, HCV replication still requires miR-122 in XRN1-depleted cells, suggesting additional functions. We also showed that miR-122 enhances HCV RNA synthesis by reducing viral genomes engaged in translation while increasing the fraction available for RNA synthesis. In this review, we summarize the recent progress on the regulatory mechanisms of HCV genome replication by miR-122.
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