Hijacking host extracellular vesicle machinery by hepatotropic viruses: current understandings and future prospects.

Recent advances in studies exploring the roles of extracellular vesicles (EVs) in viral transmission and replication have illuminated hepatotropic viruses, such as hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), and hepatitis E (HEV). While previous investigations have uncovered these viruses' ability to exploit cellular EV pathways for replication and transmission, most have focused on the impacts of exosomal pathways. With an improved understanding of EVs, four main subtypes, including exosomes, microvesicles, large oncosomes, and apoptotic bodies, have been categorized based on size and biogenic pathways. However, there remains a noticeable gap in comprehensive reviews summarizing recent findings and outlining future perspectives for EV studies related to hepatotropic viruses. This review aims to consolidate insights into EV pathways utilized by hepatotropic viruses, offering guidance for the future research direction in this field. By comprehending the diverse range of hepatotropic virus-associated EVs and their role in cellular communication during productive viral infections, this review may offer valuable insights for targeting therapeutics and devising strategies to combat virulent hepatotropic virus infections and the associated incidence of liver cancer.

Drugs of Abuse and Their Impact on Viral Pathogenesis.

Commonly misused substances such as alcohol, cocaine, heroin, methamphetamine, and opioids suppress immune responses and may impact viral pathogenesis. In recent years, illicit use of opioids has fueled outbreaks of several viral pathogens, including the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). This review focuses on the myriad of mechanisms by which drugs of abuse impact viral replication and disease progression. Virus-drug interactions can accelerate viral disease progression and lead to increased risk of virus transmission.

Mitochondria in the biology, pathogenesis, and treatment of hepatitis virus infections.

Hepatitis virus infections affect a large proportion of the global population. The host responds rapidly to viral infection by orchestrating a variety of cellular machineries, in particular, the mitochondrial compartment. Mitochondria actively regulate viral infections through modulation of the cellular innate immunity and reprogramming of metabolism. In turn, hepatitis viruses are able to modulate the morphodynamics and functions of mitochondria, but the mode of actions are distinct with respect to different types of hepatitis viruses. The resulting mutual interactions between viruses and mitochondria partially explain the clinical presentation of viral hepatitis, influence the response to antiviral treatment, and offer rational avenues for novel therapy. In this review, we aim to consider in depth the multifaceted interactions of mitochondria with hepatitis virus infections and emphasize the implications for understanding pathogenesis and advancing therapeutic development.

What Do We Know About Hepatitis Viruses in Horses?

Theiler disease (serum hepatitis or idiopathic acute hepatic necrosis) has long been suspected to have a viral etiology. Four viruses have been described in association with hepatitis in horses. Further investigation suggests equine pegivirus and Theiler disease-associated virus (a second pegivirus) are neither hepatotropic nor pathogenic. Nonprimate hepacivirus (NPHV) causes subclinical disease in experimental models and has been associated with hepatitis in some clinical cases. Equine parvovirus-hepatitis (EqPV-H) experimentally causes subclinical-to-clinical liver disease and is found in the vast majority of Theiler disease cases. EqPV-H is likely of clinical significance, whereas the significance of NPHV is unknown.

Evolutionary biology of human hepatitis viruses.

Hepatitis viruses are major threats to human health. During the last decade, highly diverse viruses related to human hepatitis viruses were found in animals other than primates. Herein, we describe both surprising conservation and striking differences of the unique biological properties and infection patterns of human hepatitis viruses and their animal homologues, including transmission routes, liver tropism, oncogenesis, chronicity, pathogenesis and envelopment. We discuss the potential for translation of newly discovered hepatitis viruses into preclinical animal models for drug testing, studies on pathogenesis and vaccine development. Finally, we re-evaluate the evolutionary origins of human hepatitis viruses and discuss the past and present zoonotic potential of their animal homologues.

Protein glycosylation in viral hepatitis-related HCC: Characterization of heterogeneity, biological roles, and clinical implications.

Protein glycosylation is one of the most frequent and well-known posttranslational modifications, playing important roles in physiopathological processes. Glycosylation is catalyzed by enzymatic additions of heterogeneous glycans with specific linkage of monosaccharides and, in a preformed fashion, to specific amino acids within glycoproteins. Altered glycan macroheterogeneity and microheterogeneity have been reported in glycoproteins produced mainly by the liver, facilitating tumorigenesis, progression, and metastasis. Characterizing the heterogeneity and biological functions of glycans in liver diseases would lead to a better understanding of the molecular pathogenesis of liver damage and cancer, providing novel diagnostic, prognostic, and therapeutic clues. Technical advances in glycoproteomics and glycomics have allowed a more comprehensive and deeper understanding of disease-related glycosylation events. Here, we briefly review the structural diversity of glycans in viral hepatitis -related hepatocellular carcinoma, discuss their roles in regulating the initiation and development of liver cancer, and introduce potential clinical applications.

Analysis of long noncoding RNA expression in hepatocellular carcinoma of different viral etiology.

BACKGROUND: Dysregulation of long noncoding RNA (lncRNA) expression contributes to the pathogenesis of many human diseases, including liver diseases. Several lncRNAs have been reported to play a role in the development of hepatocellular carcinoma (HCC). However, most studies have analyzed lncRNAs only in hepatitis B virus (HBV)-related HCC or in a single group of HCC patients regardless of the viral etiology. METHODS: To investigate whether lncRNAs are differentially expressed in HCC of different viral etiology, we profiled 101 disease-related lncRNAs, including 25 lncRNAs previously associated with HCC, in liver specimens obtained from well-characterized patients with HBV-, hepatitis C virus (HCV)-, or hepatitis D virus (HDV)-associated HCC. RESULTS: We identified eight novel HCC-related lncRNAs that were significantly dysregulated in HCC tissues compared to their surrounding non-tumorous tissues. Some of these lncRNAs were significantly dysregulated predominantly in one specific hepatitis virus-related HCC, including PCAT-29 in HBV-related HCC, aHIF and PAR5 in HCV-related HCC, and Y3 in HDV-related HCC. Among the lncRNAs previously reported in HCC, we found that DBH-AS1, hDREH and hPVT1 were differentially expressed in HCC of different viral etiology. CONCLUSIONS: Our study suggests that HCC of different viral etiology is regulated by different lncRNAs. The identification of lncRNAs unique to specific hepatitis virus-related HCC may provide new tools for improving the diagnosis of HCC and open new avenues for disease-specific therapeutic interventions.

Hepatitis Virus Infections in Poultry.

Viral hepatitis in poultry is a complex disease syndrome caused by several viruses belonging to different families including avian hepatitis E virus (HEV), duck hepatitis B virus (DHBV), duck hepatitis A virus (DHAV-1, -2, -3), duck hepatitis virus Types 2 and 3, fowl adenoviruses (FAdV), and turkey hepatitis virus (THV). While these hepatitis viruses share the same target organ, the liver, they each possess unique clinical and biological features. In this article, we aim to review the common and unique features of major poultry hepatitis viruses in an effort to identify the knowledge gaps and aid the prevention and control of poultry viral hepatitis. Avian HEV is an Orthohepevirus B in the family Hepeviridae that naturally infects chickens and consists of three distinct genotypes worldwide. Avian HEV is associated with hepatitis-splenomegaly syndrome or big liver and spleen disease in chickens, although the majority of the infected birds are subclinical. Avihepadnaviruses in the family of Hepadnaviridae have been isolated from ducks, snow geese, white storks, grey herons, cranes, and parrots. DHBV evolved with the host as a noncytopathic form without clinical signs and rarely progressed to chronicity. The outcome for DHBV infection varies by the host's ability to elicit an immune response and is dose and age dependent in ducks, thus mimicking the pathogenesis of human hepatitis B virus (HBV) infections and providing an excellent animal model for human HBV. DHAV is a picornavirus that causes a highly contagious virus infection in ducks with up to 100% flock mortality in ducklings under 6 wk of age, while older birds remain unaffected. The high morbidity and mortality has an economic impact on intensive duck production farming. Duck hepatitis virus Types 2 and 3 are astroviruses in the family of Astroviridae with similarity phylogenetically to turkey astroviruses, implicating the potential for cross-species infections between strains. Duck astrovirus (DAstV) causes acute, fatal infections in ducklings with a rapid decline within 1-2 hr and clinical and pathologic signs virtually indistinguishable from DHAV. DAstV-1 has only been recognized in the United Kingdom and recently in China, while DAstV-2 has been reported in ducks in the United States. FAdV, the causative agent of inclusion body hepatitis, is a Group I avian adenovirus in the genus Aviadenovirus. The affected birds have a swollen, friable, and discolored liver, sometimes with necrotic or hemorrhagic foci. Histologic lesions include multifocal necrosis of hepatocytes and acute hepatitis with intranuclear inclusion bodies in the nuclei of the hepatocytes. THV is a picornavirus that is likely the causative agent of turkey viral hepatitis. Currently there are more questions than answers about THV, and the pathogenesis and clinical impacts remain largely unknown. Future research in viral hepatic diseases of poultry is warranted to develop specific diagnostic assays, identify suitable cell culture systems for virus propagation, and develop effective vaccines.

In vivo models of hepatitis B and C virus infection.

Globally, more than 500 million individuals are chronically infected with hepatitis B (HBV), delta (HDV), and/or C (HCV) viruses, which can result in severe liver disease. Mechanistic studies of viral persistence and pathogenesis have been hampered by the scarcity of animal models. The limited species and cellular host range of HBV, HDV, and HCV, which robustly infect only humans and chimpanzees, have posed challenges for creating such animal models. In this review, we will discuss the barriers to interspecies transmission and the progress that has been made in our understanding of the HBV, HDV, and HCV life cycles. Additionally, we will highlight a variety of approaches that overcome these barriers and thus facilitate in vivo studies of these hepatotropic viruses.

[Microbiological diagnosis of viral hepatitis]. / Diagnóstico microbiológico de las hepatitis virales.

Liver inflammation or hepatitis has many different causes, both infectious and non-infectious. Among the former, viral infection is responsible for at least half of all hepatitis worldwide. Different viruses have been described with primary tropism for liver tissue. These microorganisms have been successively named with letters of the alphabet: A, B, C, D, E and G. The aim of this paper is to review this heterogeneous group of viruses in its most basic aspects, including clinical implications, treatment, main control, and prophylactic measures and, of special interest, diagnostic approaches, both serological and molecular, which are used for their detection, quantification and characterization.

Individuals having variant genotypes of cytochrome P450 2C19 are at increased risk of developing primary liver cancer in Han populations, without infection with the hepatitis virus.

Recently, many researchers have reported that the genetic polymorphisms of CYP2C19 may account for the interpatient variability of the clinical course in cancers including primary liver cancer (PLC). Besides the genetic polymorphisms of CYP2C19, hepatitis viruses (HV, including HAV, HBV, HCV, HDV, HEV, especially HBV and/or HCV) also account for the interpatient variability of the clinical course in PLC. This research covered the above two factors and divided the patients with PLC into two groups (one group with HBV infection and another without any HV infection) to find out whether the genetic polymorphisms of CYP2C19 have different effects in the progressing of PLC in different groups of patients. Eight hundred sixty-four cancer-free Han people (controls, named group 1), 207 Han PLC patients with HBV infection (group 2), and 55 Han PLC patients without any HV infection (group 3) were involved in this study. A wild-type allele (CYP2C19*1) and two mutated alleles (CYP2C19*2 and CYP2C19*3) were identified. The frequencies of the mutant alleles and genotypes were then compared with each other. The frequencies of the homozygous and heterozygous variant genotypes (*2/*2, *2/*3, *3/*3) in group 3 (25.5 %) were significantly higher than those in other groups (11.9 % in group 1 and 13.5 % in group 2, P = 0.014, 95 % confidence interval (CI)). The differences were statistically significant between group 1 and group 3 (P = 0.004, 95 % CI), but they were not statistically significant between group 1 and group 2 (P = 0.527, 95 % CI). Thus, we conclude that people which were not infected with HV but with the homozygous or heterozygous variant genotypes (*2/*2, *2/*3, *3/*3) of CYP2C19 may have higher possibilities of getting PLC than people with other allelic genotypes (*1/*1, *1/*2, *1/*3) (odds ratio (OR) = 2.523, 95 % CI = 1.329 ~ 4.788). However, in patients with HBV infection, the genetic polymorphisms of CYP2C19 did not seem to be an important factor in the risk of developing PLC (OR = 1.156, 95 % CI = 0.738 ~ 1.810).

Influence of interleukin-28B polymorphism on progression to hepatitis virus-induced hepatocellular carcinoma.

Genetic variation of interleukin-28B (IL-28B) rs12979860 T/C polymorphism is associated with the immune response to interferon (IFN) therapy, which is applied in the treatment of chronic viral hepatitis induced by hepatitis B virus (HBV) and hepatitis C virus (HCV). These chronic liver diseases could progress to end-stage liver diseases, such as hepatocellular carcinoma (HCC). The aim of this study was to clarify whether there exists a causal association between IL-28B rs12979860 T/C polymorphism and development of HCC. In a meta-analysis of six studies with 850 cases and 811 controls, we summarized the data on the association between IL-28B rs12979860 T/C polymorphism and HCC risk and calculated ORs and 95 % CIs to estimate the association strength. We observed that IL-28B rs12979860 T/C polymorphism was positively associated with overall HCC risk (TT vs. CC: OR = 2.38; 95 %, 1.60-3.55; TT vs CT + CC: OR = 1.79; 95 %, 1.23-2.60). In the stratified analysis by ethnicity, the robust association retained in Caucasians with higher risk among TT carriers relative to the CC carriers. A similar trend was found in the studies of healthy controls when data were stratified by source of controls. The combined data suggest that IL-28B rs12979860 T/C polymorphism seems to augment the risk of developing HCC, especially in Caucasians.

Management of hepatocellular carcinoma.

Management of hepatocellular carcinoma (HCC) is a rapidly evolving field. Advances in liver surgery and transplantation mean that curative treatment can be offered to patients with HCC in compensated livers who are diagnosed early or to those who are within transplant criteria. Explanted livers have provided a growing understanding of the underlying mechanisms in hepatocarcinogenesis and diagnostic modalities. Several locoregional therapies are also available. For advanced tumors, molecular targeted therapies are yielding promising results. Because of the heterogeneity of the patients and the disease, many questions are waiting for answers through well-designed, adequately powered, and bias-free multicenter, controlled, randomized trials.

The role of the hepatitis viruses in cholangiocarcinoma.

Cholangiocarcinoma is the second most common liver cancer in the world. The aetiology of the disease is diverse incorporating a variety of conditions leading to biliary stasis, biliary and liver inflammation, but a large number of cases still occur in the absence of established risk factors. Its incidence and mortality is increasing, which has intensified the search for alternative aetiological agents and pathogenetic mechanisms. Chronic infection with hepatitis B and hepatitis C viruses are the primary risk factor for hepatocellular cancer. This review focuses on the epidemiological evidence of a role for these viruses in cholangiocarcinoma and the pathogenetic mechanisms that might be involved.

Antiviral therapy: old and current issues.

Many antiviral drugs are currently approved and formally licensed for clinical use in the treatment of viral infections caused by human immunodeficiency virus, herpes simplex viruses, varicella-zoster virus, respiratory syncytial virus, cytomegalovirus, hepatitis B virus, hepatitis C virus or influenza virus. Recent decades have seen major advances in our knowledge of the natural history and pathogenesis of viral diseases as well as ongoing developments and improvements in antiviral therapy. However, research is far from complete and indeed previously unknown and unexpected issues are currently arising. This review aims to discuss some of these issues in the belief that they should be carefully addressed to enhance the management of patients with viral infections.

Human DEAD-box protein 3 has multiple functions in gene regulation and cell cycle control and is a prime target for viral manipulation.

The human DEAD-box RNA helicase DDX3 has been implicated to play a role in the whole repertoire of processes regulating gene expression, including transcription, splicing, mRNA export and translation. It has also been suggested to be involved in cell cycle control and the regulation of apoptosis. In addition, DDX3 was recently shown to be part of innate immune signalling pathways and to contribute to the induction of anti-viral mediators, such as type I interferon. Interestingly, DDX3 appears to be a prime target for viral manipulation: at least four different viruses, namely Hepatitis C virus (HCV), Hepatitis B virus (HBV), Human Immunodeficiency Virus (HIV) and poxviruses, encode proteins that interact with DDX3 and modulate its function. HIV and HCV seem to co-opt DDX3 and require it for their replication. It has therefore been suggested that DDX3 could be a novel target for the development of drugs against these two viruses, both of which still pose major global health threats. However, in the light of the apparent multifunctionality of DDX3 in the cell, drug development strategies targeting DDX3 will have to be carefully evaluated. This review summarises the available data on the cellular functions of DDX3 and discusses their manipulation by the different viruses known to target DDX3. Understanding the viral strategies for manipulating or co-opting DDX3 in functional and molecular detail can provide valuable insights for the development of strategies to therapeutically target DDX3.

Telomerase activity, telomere length and human telomerase reverse transcriptase expression in hepatocellular carcinoma is independent of hepatitis virus status.

BACKGROUND: Telomerase expression and the maintenance of a critical telomere length (TL) in cancer initiation indicates that telomere shortening and telomerase expression initiates cancer by induction of chromosomal instability. METHODS: Telomerase activity, TL and human telomerase reverse transcriptase (hTERT) expression were investigated in 58 hepatocellular carcinoma (HCC) and 17 chronic hepatitis patients by the telomerase repeat amplification protocol, Southern blotting and reverse transcriptase-polymerase chain reaction. RESULTS: Telomerase was positive in 76% of HCC and 11.8% of chronic hepatitis patients (P<0.0001). The mean telomere length (MTL) in HCC was significantly shorter compared with chronic hepatitis (P<0.0001). The MTL was not significantly different in HCC patients with and without cirrhosis (P=0.77). In hepatitis B virus, hepatitis C virus and non-B non-C-related HCC groups, no differences were found in telomerase activity and MTL (P=0.77). hTERT, a regulator of telomerase, was, however, positive in 81% of HCCs. The correlation between telomerase activity and hTERT mRNA expression was statistically significant (P<0.0001). The MTL in telomerase-positive HCC cases was significantly shorter than the MTL in telomerase-negative cases (P<0.0001). CONCLUSION: The majority of HCCs exhibited telomerase activity that correlated well with hTERT expression. MTL in HCC was significantly shorter than chronic hepatitis. It was also found that shorter telomeres are present in telomerase-positive HCC cases. However, no correlation was found between telomerase activity and TL with respect to the viral status in HCC.