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Volume 58, Issue 2
Displaying 1-12 of 12 articles from this issue
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Reviews
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Seigyoku GO, Mitsutoshi YONEYAMA, Takashi FUJITA2008 Volume 58 Issue 2 Pages 97-104
Published: December 24, 2008
Released on J-STAGE: August 13, 2009
JOURNAL FREE ACCESSThe innate immunity plays a crucial role in initial response to viral infection. Retinoic acid inducible gene-I (RIG-I) detects diverse viral RNAs in host cell and triggers immune response, producing antiviral cytokine, namely type I interferon (IFN). Recently, we analyzed the substrate RNAs and identified RNA binding domain of RIG-I. Here we discuss structural mechanism of intracellular RNA sensing system by RIG-I and function of RIG-I family molecules in the antiviral innate immunity.View full abstractDownload PDF (1623K) -
Takeshi SAITO, Michael Gale Jr.2008 Volume 58 Issue 2 Pages 105-116
Published: December 24, 2008
Released on J-STAGE: August 13, 2009
JOURNAL FREE ACCESSHepatitis C virus (HCV) infection is one of the most serious public health problems in the world. HCV leads patients to develop hepatic cirrhosis and precipitates hepatocellular carcinoma. HCV establishes persistent infection by impairing host innate and adaptive immune responses. HCV infected hepatocytes sense the infection through Pathogen Associated Molecular Patterns (PAMPs). The sensor molecules, Pattern Recognition Receptors (PRRs) contain two distinct categories, toll like receptors (TLR) and cytoplasmic Retinoic Acid inducible Gene I (RIG-I) like helicases (RLHs). In the hepatocyte, the cytoplasmic PRR, Retinoic Acid inducible Gene I (RIG-I) plays the central role of HCV viral genome recognition, resulting in activation of signaling to induce type I interferon and proinflammatory cytokines. Type I IFN induces more than 300 effector molecules known as interferon stimulated genes (ISGs) that establish an antiviral state in infected cells and neighboring cells. The activation of innate immunity is also critical for the mounting of innate and adaptive immunity. However, a variety of viral strategies of HCV disrupt host innate immune signaling and ISG function, resulting in a dysfunctional immune response against HCV and poor responses to the current type I IFN based therapy. Many studies have reported immune dysfunction during HCV infection in cell culture, animal models and patients. This review article focuses on understanding how the hepatic innate immunity sensor, PRR, associates with HCV PAMPs, and how HCV escapes from host immunity.View full abstractDownload PDF (733K) -
Yasushi KAWAGUCHI2008 Volume 58 Issue 2 Pages 117-124
Published: December 24, 2008
Released on J-STAGE: August 13, 2009
JOURNAL FREE ACCESSLive-cell imaging of cells infected with recombinant viruses expressing fluorescently tagged structural viral proteins enables to visualize virion maturation pathways at a virion particle level in the same cells as infection progresses. This technology have gradually unveiled previously unreported aspects of the pathways. This article focuses on live-cell imaging technology of herpes simplex virus 1 (HSV-1) and reviews the up-to-date topics of HSV-1 maturation pathway including our recent progress.View full abstractDownload PDF (448K) -
Osamu YOSHIE2008 Volume 58 Issue 2 Pages 125-140
Published: December 24, 2008
Released on J-STAGE: August 13, 2009
JOURNAL FREE ACCESSAdult T-cell leukemia (ATL) is a malignancy of mature CD4+ T cells that is etiologically associated with the infection of human T-cell leukemia virus type 1 (HTLV-1), an exogenous human retrovirus. Previously, we have shown that leukemic cells of most ATL patients express CCR4, a chemokine receptor known to be selectively expressed by T cell subsets such as Th2 cells, skin-homing memory/effector T cells, and regulatory T cells. Therefore, the expression of CCR4 suggests that ATL cells are mostly derived from one of these T cell subsets. We have also shown that Tax, the HTLV-1-encoded potent transcriptional activator, strongly induces the expression of CCL22, a CCR4 ligand, which promotes the cell-dependent transmission of HTLV-1 from HTLV-1-infected T cells to CCR4+ target T cells by inducing close cell-to-cell interactions. We have also shown that ATL cells aberrantly express the AP-1 family member Fra-2 which, by forming the heterodimer with JunD, potently induces the expression of not only CCR4 but also the genes such as c-Myb, MDM2 and Bcl-6, the well-known proto-oncogenes. Thus, Fra-2 is a novel oncogene of ATL, and CCR4 may be regarded as a useful tumor marker of ATL.View full abstractDownload PDF (1355K)
Special Issue 1 : Papillomavirus
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Takashi YUGAWA, Tohru KIYONO2008 Volume 58 Issue 2 Pages 141-154
Published: December 24, 2008
Released on J-STAGE: August 13, 2009
JOURNAL FREE ACCESSOver the last two decades since discovery of human papillomavirus (HPV) type 16 and 18 DNAs in cervical cancers by Dr. Harald zur Hausen, HPVs have been well characterized as causative agents for cervical cancer. Viral DNA from a specific group of HPVs can be detected in at least 90% of all cervical cancers and two viral genes, E6 and E7, are invariably expressed in HPV-positive cervical cancer cells. Their gene products are known to inactivate the major tumor suppressors, p53 and pRB, respectively. In addition, one function of E6 is to activate telomerase, and E6 and E7 cooperate to effectively immortalize human primary epithelial cells. Though expression of E6 and E7 is itself not sufficient for cancer development, it seems to be either directly or indirectly involved in every stage of multi-step carcinogenesis. Indeed, it has been shown that only one or two genetic alterations in addition to expression of E6 and E7 are experimentally sufficient to confer tumorigenicity to normal human cervical keratinocytes. Epidemiological and biological studies suggest the potential efficacy of prophylactic vaccines to prevent genital HPV infection as an anti-cancer strategy. However, given the widespread nature of HPV infection and unresolved issues about the duration and type specificity of the currently available HPV vaccines, it is crucial that molecular details of the natural history of HPV infection as well as the biological activities of the viral oncoproteins be elucidated in order to provide the basis for development of new therapeutic strategies against HPV-associated malignancies. This review highlights the novel functions of E6 and E7 as well as the molecular mechanisms of HPV-induced carcinogenesis.View full abstractDownload PDF (909K) -
Masaki INOUE2008 Volume 58 Issue 2 Pages 155-164
Published: December 24, 2008
Released on J-STAGE: August 13, 2009
JOURNAL FREE ACCESSResearch literature has definitively shown HPV to be a necessary cause of cervical cancer. HPV is highly prevalent in sexually active populations and its natural history is now traceable thanks to recent advances in technology. HPV-like particle can now be synthesized and assembled in vitro to constitute the major virion protein L1, and this technology has been exploited to produce HPV-L1-VLP vaccines. Now, HPV-related Diseases can thus be prevented by commercially available HPV prophylactic vaccines such as Gardasil (recombinant HPV genotype 6/11/16/18) and Cervarix (recombinant HPV genotype 16/18). These advances have dramatically changed the administration of cervical cancer screening programs.View full abstractDownload PDF (563K) -
Ayano SATSUKA, Hiroyuki SAKAI2008 Volume 58 Issue 2 Pages 165-172
Published: December 24, 2008
Released on J-STAGE: August 13, 2009
JOURNAL FREE ACCESSPapillomavirus is a pathogenic virus that induces benign tumor at the infected lesion, and its association with malignant tumor was first identified by R. Shope using animal model. A variety of cancers have been reported to be associated with the infection of human papillomavirus since the report by H. zur Hausen that describes a connection between the HPV infection and cervical cancer. The HPV infection is broadly distributed as a sexually transmitted disease (STD) and recently the initial age diagnosed as the cervical cancer is getting lowered. Because of its clinical importance, the study on HPV has been focused on the oncogenic properties, and the results of which had great impacts on the researches of the tumor suppressors, such as p53 and pRb, and "ubiquiitn-proteasome" pathway. On the other hand, the biological properties of HPV remain mostly disclosed. The lifecycle of HPV is tightly linked to the differentiation program of the target epithelial cell, and this unique property has hampered the study on the HPV replication mechanism. Here we summarized the findings on the HPV lifecycle, including the virus gene functions, the regulation of viral gene expression and replication.View full abstractDownload PDF (1542K) -
Kiyofumi EGAWA2008 Volume 58 Issue 2 Pages 173-182
Published: December 24, 2008
Released on J-STAGE: August 13, 2009
JOURNAL FREE ACCESSMore than 100 HPV genotypes are presently distinguished by comparing the DNA sequence of the L1 ORF of each HPV.
Two important aspects of the nature of this group of heterogeneous viruses are the way in which specific HPV genotypes are associated with distinct clinical and histological morphologies and the way specific HPV genotypes affect distinct anatomical sites.
The former is best evidenced by the HPV type specific cytopathic or cytopathogenic effect (CPE), whereas the latter is suggested by the marked preference of each HPV genotype for specific tissues and sites. Recent studies have also suggested that specific HPV genotypes may target epithelial stem cells at specific anatomical sites.
HPV type-specific CPE is the central schema when we analyze and understand the HPV-associated diseases. The concept was suggested by the characterization of distinct HPVs from different types of warts: HPV 2/27/57 from common warts, HPV 3/10/28 from flat warts, HPV 6/11 from condyloma acuminatum, and HPV 5/8 from lesions of epidermodysplasia verruciformis (EV).
In this paper, I summarize recent advances in HPV study field, especially on HPV-associated cutaneous lesions. These include inclusion warts, HPV-associated epidermoid cysts, HPV type specific activation of melanogenesis, a double infection with HPV 1 and HPV 63 within a single cell, primary target cells and life cycle of the virus, and the identification of novel genes that are associated EV.
The HPV-associated cutaneous lesions thus pose important problems to be resolved in virology and human pathology.View full abstractDownload PDF (558K)
Special Issue 2 : HCV oncogenesis and treatment
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Kohji MORIISHI, Yoshio MORI, Yoshiharu MATSUURA2008 Volume 58 Issue 2 Pages 183-190
Published: December 24, 2008
Released on J-STAGE: August 13, 2009
JOURNAL FREE ACCESSHepatitis C virus (HCV) is a major causative agent of blood-borne hepatitis. Most of the HCV-positive individuals have been chronically infected with the virus for decades, leading to development of steatosis, cirrhosis and ultimately hepatocellular carcinoma. In addition, cryoglobulinemia and type 2 diabetes mellitus are associated with a chronic infection with HCV. Hepatocellular carcinoma induced by HCV infection is not caused by only the repeated inflammations but also the biological activity of HCV proteins. HCV core protein has been reported as a component of the viral nucleocapsid as well as the pathogenic factor that could induce the production of oxidative stress and progression of cell growth. In this review, we summarize the current status of our knowledge regarding to the processing and pathogenicity of HCV core protein.View full abstractDownload PDF (319K) -
Nobuyuki KATO2008 Volume 58 Issue 2 Pages 191-198
Published: December 24, 2008
Released on J-STAGE: August 13, 2009
JOURNAL FREE ACCESSThe studies on the mechanism of HCV replication proliferated after the development of cell culture based-subgenomic HCV replicon system and genome-length HCV RNA replication system. Furthermore, these RNA replication systems have been improved to be suitable systems for the screening of anti-HCV reagents by the introduction of reporter genes such as luciferase. Genetic analysis of HCV RNAs obtained in long-term cell culture of HCV replicon or genome-length HCV RNA-harboring cells revealed that genetic mutations in HCV RNAs accumulated in a time-dependent manner. The genetic diversity of HCVs was also enlarged in a time-dependent manner. The appearance of adaptive mutation in HCV replicon or genome-length HCV RNA is one of characteristic features of HCV RNA replication system. Although human hepatoma-derived HuH-7 cell line was mainly used for HCV RNA replication systems, a specific combination of adaptive mutations led to develop the HCV RNA replication systems using a new human hepatoma cell line other than HuH-7.View full abstractDownload PDF (349K) -
Tetsuro SUZUKI, Takahiro MASAKI, Hideki AIZAKI2008 Volume 58 Issue 2 Pages 199-206
Published: December 24, 2008
Released on J-STAGE: August 13, 2009
JOURNAL FREE ACCESSA robust system for production of recombinant infectious hepatitis C virus (HCV) has been established in 2005 and classical virological techniques are now able to be applied to the HCV research, especially regarding molecular mechanisms on virion assembly and maturation. We recently demonstrated that the C-terminal serine cluster of NS5A is a determinant of NS5A interaction with Core and the subcellular localization of NS5A. Mutation of this cluster blocks the NS5A-Core interaction, resulting in perturbation of association between Core and HCV RNA. It is thus tempting to consider that NS5A plays a key role in transporting the viral genome RNA synthesized by the replication complex to the surface of lipid droplets (LDs) or LD-associated membranes, where Core localizes, leading to facilitation of nucleocapsid formation. We also demonstrated an important role of cholesterol and sphingolipid in HCV infection and virion maturation. Specifically, mature HCV particles are rich in cholesterol. Depletion of cholesterol from HCV or hydrolysis of virion-associated sphingomyelin results in a loss of infectivity, and the addition of exogenous cholesterol restores infectivity. In addition, cholesterol and sphingolipid on the HCV membrane play a key role in virus internalization. Finally, inhibitors of the sphingolipid biosynthetic pathway efficiently block virion production.View full abstractDownload PDF (516K) -
Yuichi HIRATA, Masayuki SUDOH, Michinori KOHARA2008 Volume 58 Issue 2 Pages 207-214
Published: December 24, 2008
Released on J-STAGE: August 13, 2009
JOURNAL FREE ACCESSHepatitis C virus(HCV) develops persistent infection in most infected patients, and eventually cause chronic hepatitis, liver cirrhosis and then hepatocellular carcinoma. The combination therapy of PEG-IFN and ribavirin improves the efficacy in many patients, while it does not lead to sufficient achievements in genotype1b patients. To invent new anti-HCV reagent, we focused on host factors which HCV take advantage of in its life-cycle. We identified serine palmitoyltransferase inhibitor as anti-HCV reagent through high-through put screenig using HCV replicon cells. Moreover, we evaluate the anti-HCV effect of SPT-inhibitor in vivo with humanized chimeric mice. SPT-inhibitor led to rapid decline in serum HCV-RNA of about 1-2log within 8 day, futhermore the combination therapy of SPT-inhibitor and PEG-IFN achieved about 3log reduction in serum HCV-RNA. At last, we investigated the mechanism of anti-HCV effect of SPT-inhibitor. It has been reported that sphingolipids and cholesterol compose the lipid raft, in which the replication of HCV occur. We investigated the influence of SPT-inhibitor to lipid rafts by analysing the detergent resistant membrane(DRM) . The analysis proved that SPT inhibitor got HCV RNA dependent RNA polymerase (NS5B) to move to detergent soluble fraction from DRM, and Biacore analysis indicated the binding of sphingomyelin to NS5B. These results suggested SPT inhibitor got NS5B to release from replication complex.View full abstractDownload PDF (1493K)
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