Strategies for Antiviral Screening Targeting Early Steps of Virus Infection

Viral infection begins with the entry of the virus into the host target cell and initiates replication. For this reason, the virus entry machinery is an excellent target for antiviral therapeutics. In general, a virus life cycle includes several major steps: cell-surface attachment, entry, replication, assembly, and egress, while some viruses involve another stage called latency. The early steps of the virus life cycle include virus attachment, receptor binding, and entry. These steps involve the initial interactions between a virus and the host cell and thus are major determinants of the tropism of the virus infection, the nature of the virus replication, and the diseases resulting from the infection. Owing to the pathological importance of these early steps in the progress of viral infectious diseases, the development of inhibitors against these steps has been the focus of the pharmaceutical industry. In this review, Herpes Simplex Virus (HSV), Hepatitis C Virus (HCV), and Human Enterovirus 71 (EV71) were used as representatives of enveloped DNA, enveloped RNA, and non-enveloped viruses, respectively. The current mechanistic understanding of their attachment and entry, and the strategies for antagonist screenings are summarized herein.

Involvement of autophagy in alcoholic liver injury and hepatitis C pathogenesis

This review describes the principal pathways of macroautophagy (i.e. autophagy), microautophagy and chaperone-mediated autophagy as they are currently known to occur in mammalian cells. Because of its crucial role as an accessory digestive organ, the liver has a particularly robust autophagic activity that is sensitive to changes in plasma and dietary components. Ethanol consumption causes major changes in hepatic protein and lipid metabolism and both are regulated by autophagy, which is significantly affected by hepatic ethanol metabolism. Ethanol exposure enhances autophagosome formation in liver cells, but suppresses lysosome function. Excessive ethanol consumption synergizes with hepatitis C virus (HCV) to exacerbate liver injury, as alcohol-consuming HCV patients frequently have a longer course of infection and more severe manifestations of chronic hepatitis than abstinent HCV patients. Alcohol-elicited exacerbation of HCV infection pathogenesis is related to modulation by ethanol metabolism of HCV replication. Additionally, as part of this mechanism, autophagic proteins have been shown to regulate viral (HCV) replication and their intracel-lular accumulation. Because ethanol induces autophagosome expression, enhanced levels of autophagic proteins may enhance HCV infectivity in liver cells of alcoholics and heavy drinkers.

Visualization of the Oncolytic Alphavirus M1 Life Cycle in Cancer Cells

Oncolytic alphavirus M1 has been shown to selectively target and kill cancer cells,but cytopathic morphologies induced by M1 virus and the life cycle of the M1 strain in cancer cells remain unclear.Here,we study the key stages of M1 virus infection and replication in the M1 virus-sensitive HepG2 liver cancer cell line by transmission electron microscopy,specifically examining viral entry,assembly,maturation and release.We found that M1 virus induces vacuolization of cancer cells during infection and ultimately nuclear marginalization,a typical indicator of apoptosis.Specifically,our results suggest that the endoplasmic reticulum participates in the assembly of nucleocapsids.In the early and late stage of infection,three kinds of special cytopathic vacuoles are formed and appear to be involved in the replication,maturation and release of the virus.Taken together,our data displayed the process of M1 virus infection of tumor cells and provide the structural basis for the study of M1 virus-host interactions.

Hepatitis B virus molecular biology and pathogenesis

As obligate intracellular parasites,viruses need a host cell to provide a milieu favorable to viral replication.Consequently,viruses often adopt mechanisms to subvert host cellular signaling processes.While beneficial for the viral replication cycle,virus-induced deregulation of host cellular signaling processes can be detrimental to host cell physiology and can lead to virus-associated pathogenesis,including,for oncogenic viruses,cell transformation and cancer progression.Included among these oncogenic viruses is the hepatitis B virus(HBV).Despite the availability of an HBV vaccine,350-500 million people worldwide are chronically infected with HBV,and a significant number of these chronically infected individuals will develop hepatocellular carcinoma(HCC).Epidemiological studies indicate that chronic infection with HBV is the leading risk factor for the development of HCC.Globally,HCC is the second highest cause of cancer-associated deaths,underscoring the need for understanding mechanisms that regulate HBV replication and the development of HBV-associated HCC.HBV is the prototype member of the Hepadnaviridae family;members of this family of viruses have a narrow host range and predominately infect hepatocytes in their respective hosts.The extremely small and compact hepadnaviral genome,the unique arrangement of open reading frames,and a replication strategy utilizing reverse transcription of an RNA intermediate to generate the DNA genome are distinguishing features of the Hepadnaviridae.In this review,the authors provide a comprehensive description of HBV biology,summarize the model systems used for studying HBV infections,and highlight potential mechanisms that link a chronic HBV-infection to the development of HCC.For example,the HBV X protein(HBx),a key regulatory HBV protein that is important for HBV replication,is thought to play a cofactor role in the development of HBV-induced HCC,and the authors highlight the functions of HBx that may contribute to the development of HBV-associated HCC.