Quantifying HTLV-I dynamics

Despite significant advances in our understanding of the immune response to persistent viruses like human T-cell lymphotropic virus type I (HTLV-I), many important questions remain unanswered. Mathematical modelling enables us to interpret and synthesise diverse experimental data in new ways and thus can contribute to our understanding. Here, we review recent advances in mathematical modelling of HTLV-I infection and illustrate how mathematics has enabled us to identify factors that determine an individual's viral burden and risk of developing HTLV-I-associated diseases.     

Immunology of hepatitis B virus and hepatitis C virus infection

More than 500 million people worldwide are persistently infected with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV) and are at risk of developing chronic liver disease, cirrhosis and hepatocellular carcinoma. Despite many common features in the pathogenesis of HBV- and HCV-related liver disease, these viruses markedly differ in their virological properties and in their immune escape and survival strategies. This review assesses recent advances in our understanding of viral hepatitis, contrasts mechanisms of virus-host interaction in acute hepatitis B and hepatitis C, and outlines areas for future studies.     

IFITMs Restrict the Replication of Multiple Pathogenic Viruses

The interferon-inducible transmembrane protein (IFITM) family inhibits a growing number of pathogenic viruses, among them influenza A virus, dengue virus, hepatitis C virus, and Ebola virus. This review covers recent developments in our understanding of the IFITM's molecular determinants, potential mechanisms of action, and impact on pathogenesis.     

Chronic HBV-related liver disease

Thirty years after its discovery, the hepatitis B virus (HBV) still remains a major global public health problem. Worldwide, two billion subjects have been infected, 300 million have a chronic infection and more than 600,000 die annually of HBV-related liver disease or hepatocellular carcinoma; new infections occur because of the presence of a large reservoir of chronic carriers of the virus. The knowledge of the HBV organization and replication cycle and the availability of sensitive HBV-DNA assays have led to remarkable progress in our understanding of the natural history of chronic hepatitis B infections. Crucial to the prevention of new infections, to the management and the monitoring of HBV carriers and to the choice of best treatment strategy, is the understanding of the natural dynamism of HBV infection and of the virus-host interactions that induce liver damage.     

Interferon signaling in the liver during hepatitis C virus infection

Hepatitis C virus is a global health concern, estimated to infect 2-3% of the world's population. Inter-individual differences in the course of infection and response to therapy, highlighted by recent genomewide association studies, point to the crucial role of the host immune system in the efficient control of infection. Ongoing progress in the studies of the role of innate immunity during hepatitis C virus infection has improved our understanding of the intricacies of the host-virus interactions. In this review, we summarize and discuss the current knowledge concerning interferon signaling in the liver during acute and chronic hepatitis C virus infection and its implications for the outcome of interferon-α-based antiviral therapies.     

MicroRNA in HCV infection and liver cancer

In the more than two-decades since hepatitis C virus (HCV) was identified, there has been considerable improvement in our understanding of virus life cycle due largely to the development of in vitro culture systems for virus replication. Still challenges remain: HCV infection is a major risk factor for chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide; yet mechanistic details of HCV infection-associated hepatocarcinogenesis remain incompletely understood. A protective vaccine is not yet available, and current therapeutic options result in sustained virus clearance only in a subset of patients. Recent interest has focused on small non-protein coding RNAs, microRNAs (miRNAs), the dependence of virus replication on miRNAs, and miRNA-regulated genes in liver cancer. Functional analysis of the miRNA-targeted genes in liver cancer has advanced our understanding of the "oncomiRs" and their role in hepatocarcinogenesis. This review focuses on the dependence of HCV replication on miRNA and role of miRNA-targeted tumor suppressor genes as molecular markers of and possible targets for developing oncomiR-targeted therapy of chronic hepatitis and HCC. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation.     

从动物模型看乙型病毒性肝炎致病机制的研究进展

乙型肝炎病毒(Hepatitis B virus,HBV)是通过血液和体液传播的嗜肝DNA病毒,尽管有有效的预防疫苗,乙型病毒性肝炎仍是我国乃至全球人类健康的重大威胁。HBV的易感宿主只局限于人以及黑猩猩等灵长类动物,HBV感染性疾病的研究遇到很大困难。多种小动物研究模型的建立,使我们对HBV感染致病机制的认识有了很大进步,包括:分子病毒学特征、在感染细胞中生命周期、机体的抗病毒免疫反应、肝脏病变的免疫病理机制等。但是,由于已有动物模型的种种限制,我们对HBV感染及乙型肝炎发生和发展的认识还远远不够,目前除了抗病毒治疗外,还没有有效地治疗慢性乙肝的方法。建立能够真实反映临床HBV感染、乙肝发生和进展过程的纯系小鼠模型,对于我们全面深入地理解HBV感染的侵入机制、宿主和病毒之间相互作用,以及发展预防和治疗HBV感染的新方法都具有非常重要的意义。     

Antiviral activity of interferon-alpha against hepatitis B virus can be studied in non-hepatic cells and Is independent of MxA.

It is well established that interferon-alpha can induce non-cytotoxic intracellular suppression of hepatitis B virus replication, but the mechanisms involved are unclear. Cell culture studies to characterize these mechanisms are restricted, in part because hepatitis B virus replicates almost exclusively in liver-derived cells. To overcome this limitation we used a cytomegalovirus promoter-controlled hepatitis B virus expression system, which leads to intracellular viral replication even in non-hepatic cell lines. In this experimental system interferon-alpha treatment specifically suppressed viral replication demonstrating that antiviral activities against hepatitis B virus are not restricted to hepatic cells. Furthermore, the interferon-inducible MxA protein was recently reported to play a key role in the antiviral action of interferon-alpha against hepatitis B virus. Our data demonstrate that interferon-alpha also suppresses hepatitis B virus replication in MxA-deficient HEp2 cells, indicating that MxA is not essential for these activities. Taken together, our data imply that the experimental approach presented can also be adapted to established cell lines which are deficient in parts of the signal transduction pathway or other elements located further downstream, providing important insights into mechanisms specifically suppressing hepatitis B virus.     

Dynamics of hepatitis B virus infection

Mathematical models of the dynamics of HIV and hepatitis C virus infection have proven to be of great utility in understanding pathogenesis and designing better treatments. Here, we review the state of the art in modeling and interpreting data obtained from hepatitis B virus infected patients treated with antiviral agents.     

Public, private and non-specific antibodies induced by non-cytopathic viral infections

Lymphocytic choriomeningitis virus (LCMV) represents a useful experimental model of murine infection with a non-cytopathic virus, bearing resemblance to HIV and hepatitis C virus (HCV) infections in humans. Recent data from the LCMV model indicate that the humoral immune response that is induced by non-cytopathic viruses is far more complex than previously appreciated. LCMV-induced IgG production is largely polyclonal, with more than 90% of the antibody repertoire constituting non-relevant specificities. A delayed virus-neutralizing antibody response is induced, including specificities directed not only against the parental LCMV-strain present in the host but also cross-specifically against LCMV-variants isolated from other hosts. These findings provide novel insights to aid our understanding of clinically relevant observations that are recorded following human infection with HIV, HCV and dengue viruses.     

The evolution of epidemic influenza

Recent developments in complete-genome sequencing, antigenic mapping and epidemiological modelling are greatly improving our knowledge of the evolution of human influenza virus at the epidemiological scale. In particular, recent studies have revealed a more complex relationship between antigenic evolution, natural selection and reassortment than previously realized. Despite these advances, there is much that remains to be understood about the epidemiology of influenza virus, particularly the processes that determine the virus's strong seasonality. We argue that a complete understanding of the evolutionary biology of this important human pathogen will require a genomic view of genetic diversity, including the acquisition of polymorphism data from within individual hosts and from geographical regions, particularly the tropics, which have been poorly surveyed to date.     

Quasispecies Theory and the Behavior of RNA Viruses

A large number of medically important viruses, including HIV, hepatitis C virus, and influenza, have RNA genomes. These viruses replicate with extremely high mutation rates and exhibit significant genetic diversity. This diversity allows a viral population to rapidly adapt to dynamic environments and evolve resistance to vaccines and antiviral drugs. For the last 30 years, quasispecies theory has provided a population-based framework for understanding RNA viral evolution. A quasispecies is a cloud of diverse variants that are genetically linked through mutation, interact cooperatively on a functional level, and collectively contribute to the characteristics of the population. Many predictions of quasispecies theory run counter to traditional views of microbial behavior and evolution and have profound implications for our understanding of viral disease. Here, we discuss basic principles of quasispecies theory and describe its relevance for our understanding of viral fitness, virulence, and antiviral therapeutic strategy.     

The design of a potent inhibitor of the hepatitis C virus NS3 protease: BILN 2061--from the NMR tube to the clinic

The virally encoded serine protease NS3/NS4A is essential to the life cycle of the hepatitis C virus (HCV), an important human pathogen causing chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma. Until very recently, the design of inhibitors for the HCV NS3 protease was limited to large peptidomimetic compounds with poor pharmacokinetic properties, making drug discovery an extremely challenging endeavor. In our quest for the discovery of a small-molecule lead that could block replication of the hepatitis C virus by binding to the HCV NS3 protease, the critical protein-polypeptide interactions between the virally encoded NS3 serine protease and its polyprotein substrate were investigated. Lead optimization of a substrate-based hexapeptide, guided by structural data, led to the understanding of the molecular dynamics and electronic effects that modulate the affinity of peptidomimetic ligands for the active site of this enzyme. Macrocyclic beta-strand scaffolds were designed that allowed the discovery of potent, highly selective, and orally bioavailable compounds. These molecules were the first HCV NS3 protease inhibitors reported that inhibit replication of HCV subgenomic RNA in a cell-based replicon assay at low nanomolar concentrations. Optimization of their biopharmaceutical properties led to the discovery of the clinical candidate BILN 2061. Oral administration of BILN 2061 to patients infected with the hepatitis C genotype 1 virus resulted in an impressive reduction of viral RNA levels, establishing proof-of-concept for HCV NS3 protease inhibitors as therapeutic agents in humans.     

Interaction between hepatitis C virus proteins and host cell factors

Since the discovery of the hepatitis C virus (HCV) as the causative agent of non-A, non-B hepatitis, significant effort has been devoted to understanding this important pathogen. Despite the difficulty in culturing this virus efficiently, much is known about the organization of the viral genome and the functions of many of the viral proteins. Through the use of surrogate expression systems combined with cellular fractionation, pull-down experiments and yeast two-hybrid screens, numerous interactions between hepatitis C virus proteins and cellular components have been identified. The relevance of many of these interactions to hepatitis C biology remains to be demonstrated. This review discusses recent developments in this area of HCV research.     

Hepatitis C virus budding at lipid droplet-associated ER membrane visualized by 3D electron microscopy

The mechanisms underlying hepatitis C virus (HCV) morphogenesis remain elusive, but lipid droplets have recently been shown to be important organelles for virus production. We investigated the interaction between HCV-like particles and lipid droplets by three-dimensional reconstructions of serial ultrathin electron microscopy sections of cells producing the HCV core protein. The budding of HCV-like particles was mostly initiated at membranes close to the lipid droplets rather than at membranes directly apposed to the lipid droplets. This may have important implications for our understanding of the complex relationship between HCV and lipids and may make easier to dissect out the HCV life cycle.     

Hepatitis C virus (HCV) employs multiple strategies to subvert the host innate antiviral response

Hepatitis C virus (HCV) is a serious global health problem which accounts for approximately 40% of chronic liver diseases worldwide. HCV frequently establishes a persistent infection, although it is recognized and targeted by innate immunity as well as cellular and humoral immune mechanisms. This suggests that HCV has developed powerful strategies to escape elimination by innate and adaptive immunity. HCV-induced liver injury is thought to be mainly immune-mediated rather than due to direct cytopathic effects of the virus. Hence, therapeutic strategies should target those mechanisms favoring viral persistence since unspecific enhancement of host antiviral immunity may theoretically also promote liver injury. The present review summarizes our current understanding of how the hepatitis C virus interferes with the innate antiviral host-response to establish persistent infection.     

Antagonism of the interferon-induced OAS-RNase L pathway by murine coronavirus ns2 protein is required for virus replication and liver pathology

Many viruses induce hepatitis in humans, highlighting the need to understand the underlying mechanisms of virus-induced liver pathology. The murine coronavirus, mouse hepatitis virus (MHV), causes acute hepatitis in its natural host and provides a useful model for understanding virus interaction with liver cells. The MHV accessory protein, ns2, antagonizes the type I interferon response and promotes hepatitis. We show that ns2 has 2',5'-phosphodiesterase activity, which blocks the interferon inducible 2',5'-oligoadenylate synthetase (OAS)-RNase L pathway to facilitate hepatitis development. Ns2 cleaves 2',5'-oligoadenylate, the product of OAS, to prevent activation of the cellular endoribonuclease RNase L and consequently block viral RNA degradation. An ns2 mutant virus was unable to replicate in the liver or induce hepatitis in wild-type mice, but was highly pathogenic in RNase L deficient mice. Thus, RNase L is a critical cellular factor for protection against viral infection of the liver and the resulting hepatitis.     

Response of primed human PBMC to synthetic peptides derived from hepatitis B virus envelope proteins: a search for promiscuous epitopes

This investigation was aimed at identifying effective T helper cell epitopes to the hepatitis B virus in humans. A panel of synthetic peptides that represent the hepatitis B virus whole envelope proteins was examined for their capability to stimulate peripheral blood mononuclear cells from human subjects infected with hepatitis B virus naturally. In addition, a large number of subjects were examined and their human leukocyte antigen (HLA) class II allele types were identified to determine whether the helper T cell epitope is specific for a particular HLA allele or 'promiscuous'. The peptides of the amino acid residues 52-67, 110-125, 190-205, and 228-243 appeared to be immunogenic, and particularly, the 52-67 residue was the most promiscuous epitope peptide. These results would contribute to the better understanding of the helper T cell responses to the hepatitis B virus and provide a useful way in designing epitope-based vaccines and future therapeutic strategies.     

Palaeopathology and genes: Investigating the genetics of infectious diseases in excavated human skeletal remains and mummies from past populations

The aim of this paper is to review the use of genetics in palaeomicrobiology, and to highlight the importance of understanding past diseases. Palaeomicrobiology is the study of disease pathogens in skeletal and mummified remains from archaeological contexts. It has revolutionarised our understanding of health in the past by enabling a deeper knowledge of the origins and evolution of many diseases that have shaped us as a species. Bacterial diseases explored include tuberculosis, leprosy, bubonic plague, typhoid, syphilis, endemic and epidemic typhus, trench fever, and Helicobacter pylori. Viral diseases discussed include influenza, hepatitis B, human papilloma virus (HPV), human T-cell lymphotrophic virus (HTLV-1) and human immunodeficiency virus (HIV). Parasitic diseases investigated include malaria, leishmaniasis, Chagas' disease, roundworm, whipworm, pinworm, Chinese liver fluke, fleas and lice. Through a better understanding of disease origins and their evolution, we can place into context how many infectious diseases are changing over time, and so help us estimate how they may change in the future.