Hepatitis C virus infection as a risk factor for Parkinson disease: A nationwide cohort study.

OBJECTIVE: To determine whether hepatitis C virus (HCV) infection is a risk factor for developing Parkinson disease (PD).
METHODS: This nationwide population-based cohort study was based on data obtained from a dataset of the Taiwan National Health Insurance Research Database for the period 2000 to 2010. A total of 49,967 patients with viral hepatitis were included for analysis. Furthermore, 199,868 people without viral hepatitis were
included for comparisons. Patients with viral hepatitis were further grouped into 3 cohorts: hepatitis B virus (HBV) infection, HCV infection, and HBV-HCV coinfection. In each cohort, we calculated the incidence of developing PD. A Cox  proportional hazards model was applied to estimate the risk of developing PD in terms of hazard ratios (HRs) and 95% confidence intervals (CIs).
RESULTS: The crude HRs for developing PD was 0.66 (95% CI = 0.55-0.80) for HBV infection, 2.50 (95% CI = 2.07-3.02) for HCV infection, and 1.28 (95% CI = 0.88-1.85) for HBV-HCV coinfection. The association between HCV and PD remained statistically significant after adjustments for age, sex, and comorbidities (adjusted HR = 1.29, 95% CI = 1.06-1.56).
CONCLUSIONS:We conducted a large nationwide population-based study and found that patients with HCV exhibit a significantly increased risk of developing PD.

© 2015 American Academy of Neurology.

Reduced cerebral cortical thickness in Non-cirrhotic patients with hepatitis C. - PubMed - NCBI

Hepatitis C virus (HCV) infection is associated with fatigue, depression, and cognitive impairment even in the absence of severe liver fibrosis or cirrhosis. HCV has been hypothesised to cause neurodegenerative changes through low-grade neuroinflammation. Our aim was to examine whether cortical thickness (CTh) differs between chronic HCV patients and healthy controls, suggestive of cortical atrophy. In this case-control study 43 HCV patients without severe liver fibrosis, substance abuse, or comorbid HIV or hepatitis B virus infection, and 43 age and sex matched controls underwent MRI. Cortical thickness was measured using a surface based approach. Participants underwent semi-structured psychiatric interview and fatigue was assessed using the fatigue severity scale. HCV was associated with higher fatigue scores, and 58 % of HCV patients suffered from significant fatigue (p < 0.0001). Depression was observed in 16 % of patients. Areas of significantly reduced CTh were found in both left and right occipital cortex and in the left frontal lobe after correction for multiple comparisons (p < 0.05). No association between fatigue, former substance abuse, or psychotropic medication and CTh was found. No overall difference in cerebral white and grey matter volume was found. The findings support the hypothesis that HCV is associated with neurodegenerative changes.

Combatting Viruses with RNA-Targeted CRISPR | The Scientist Magazine®

The list of potential uses for the CRISPR/Cas system grows longer by
the day. Now fighting viruses may soon be added to that list, according
to a study published today (April 27) in PNAS. Microbiologist David Weiss and immunologist Arash Grakoui of Emory University in Atlanta and their colleagues used a version of the Cas9 enzyme from the bacteria Francisella novicida to bind hepatitis C virus (HCV) RNA and prevent the pathogen from replicating inside human cells.



Last summer, another group showed that CRISPR/Cas9 could be used to seek out and excise HIV DNA from the genomes of latently-infected cells. The Emory team later found that F. novicida
Cas9 (FnCas9) blocks HCV in a different way; it binds viral RNA in the
cytosol such that, “if there are off-target effects, it wouldn’t be
editing the genome,” said study coauthor Aryn Price, a graduate student in Grakoui’s lab.

Hepatitis C virus infection: a risk factor for Parkinson's disease. - PubMed - NCBI

Recent studies found that hepatitis C virus (HCV) may invade the central nervous system, and both HCV and Parkinson's disease (PD) have in common the overexpression of inflammatory biomarkers. We analysed data from a community-based integrated screening programme based on a total of 62 276 subjects. We used logistic regression models to investigate association between HCV infection and PD. The neurotoxicity of HCV was evaluated in the midbrain neuron-glia coculture system in rats. The cytokine/chemokine array was performed to measure the differences of amounts of cytokines released from midbrain in the presence and absence of HCV. The crude odds ratios (ORs) for having PD were 0.62 [95% confidence interval (CI), 0.48-0.81] and 1.91 (95% CI, 1.48-2.47) for hepatitis B virus (HBV) and HCV. After controlling for potential confounders, the association between HCV and PD remained statistically significant (adjusted OR = 1.39; 95% CI, 1.07-1.80), but not significantly different between HBV and PD. The HCV induced 60% dopaminergic neuron death in the midbrain neuron-glia coculture system in rats, similar to that of 1-methyl-4-phenylpyridinium (MPP+ ) but not caused by HBV. This link was further supported by the finding that HCV infection may release the inflammatory cytokines, which may play a role in the pathogenesis of PD. In conclusion, our study demonstrated a significantly positive epidemiological association between HCV infection and PD and corroborated the dopaminergic toxicity of HCV similar to that of MPP+ 

Endocannabinoid CB1 antagonists inhibit hepatitis C virus production, providing a novel class of antiviral host targeting agents.

Direct acting antivirals have significantly improved treatment outcomes
in chronic hepatitis C (CHC), but side effects, drug resistance and cost
mean that better treatments are still needed. Lipid metabolism is
closely linked with hepatitis C virus (HCV) replication and
endocannabinoids are major regulators of lipid homeostasis. The
cannabinoid 1 (CB1) receptor mediates these effects in the liver. We
have previously shown up-regulation of CB1 receptors in the livers of
patients with CHC, and in a HCV cell culture model. Here we investigated
whether CB1 blockade inhibits HCV replication. The antiviral effect of a
CB1 antagonist, AM251 was examined in the JFH1 cell culture and
subgenomic replicon models. The effects on the expression of genes
involved in lipid metabolism were also measured. CB1 shRNA was used to
confirm that the effects were specific for the cannabinoid receptor.
Treatment with AM251 strongly inhibited HCV RNA (~70%), viral protein
(~80%), the production of new virus particles (~70%), and virus
infectivity (~90%). As expected, AM251 reduced the expression of
pro-lipogenic genes (SREBP-1c, FASN, SCD1 and ACC1) and stimulated genes
promoting lipid oxidation (CPT1 and PPARα). This effect was mediated by
AMPK. Stable CB1 knockdown of cells infected with HCV showed reduced
levels of HCV RNA, compared with controls. Reduced CB1 signalling
inhibits HCV replication using either pharmacological inhibitors or CB1
shRNA. This may be due, at least in part, to reduced lipogenesis,
mediated by AMPK activation. We suggest that CB1 antagonists may
represent an entirely new class of drugs with activity against HCV.

Network-based study reveals potential infection pathways of hepatitis-C leading to various diseases.

Protein-protein interaction network-based study of viral pathogenesis
has been gaining popularity among computational biologists in recent
days. In the present study we attempt to investigate the possible
pathways of hepatitis-C virus (HCV) infection by integrating the
HCV-human interaction network, human protein interactome and human
genetic disease association network. We have proposed quasi-biclique and
quasi-clique mining algorithms to integrate these three networks to
identify infection gateway host proteins and possible pathways of HCV
pathogenesis leading to various diseases. Integrated study of three
networks, namely HCV-human interaction network, human protein
interaction network, and human proteins-disease association network
reveals potential pathways of infection by the HCV that lead to various
diseases including cancers. The gateway proteins have been found to be
biologically coherent and have high degrees in human interactome
compared to the other virus-targeted proteins. The analyses done in this
study provide possible targets for more effective anti-hepatitis-C
therapeutic involvement.

Apolipoprotein E Codetermines Tissue Tropism of Hepatitis C Virus and Is Crucial for Viral Cell-to-Cell Transmission by Contributing to a Postenvelopment Step of Assembly

Hepatitis C virus (HCV) predominantly infects human hepatocytes, although extrahepatic virus reservoirs are being discussed. Infection of cells is initiated via cell-free and direct cell-to-cell transmission routes. Cell type-specific determinants of HCV entry and RNA replication have been reported. Moreover, several host factors required for synthesis and secretion of lipoproteins from liver cells, in part expressed in tissue-specific fashion, have been implicated in HCV assembly. However, the minimal cell type-specific requirements for HCV assembly have remained elusive. Here we report that production of HCV trans-complemented particles (HCVTCP) from nonliver cells depends on ectopic expression of apolipoprotein E (ApoE). For efficient virus production by full-length HCV genomes, microRNA 122 (miR-122)-mediated enhancement of RNA replication is additionally required. Typical properties of cell culture-grown HCV (HCVcc) particles from ApoE-expressing nonliver cells are comparable to those of virions derived from human hepatoma cells, although specific infectivity of virions is modestly reduced. Thus, apolipoprotein B (ApoB), microsomal triglyceride transfer protein (MTTP), and apolipoprotein C1 (ApoC1), previously implicated in HCV assembly, are dispensable for production of infectious HCV. In the absence of ApoE, release of core protein from infected cells is reduced, and production of extracellular as well as intracellular infectivity is ablated. Since envelopment of capsids was not impaired, we conclude that ApoE acts after capsid envelopment but prior to secretion of infectious HCV. Remarkably, the lack of ApoE also abrogated direct HCV cell-to-cell transmission. These findings highlight ApoE as a host factor codetermining HCV tissue tropism due to its involvement in a late assembly step and viral cell-to-cell transmission.

Hepatitis C viral infection and the risk of dementia.

BACKGROUND AND PURPOSE:

Hepatitis C virus (HCV) infection may cause cognitive impairment, but no studies have focused specifically on cognitive impairment stemming from HCV. The purpose of this study was to investigate the potential increased risk for dementia in HCV-infected patients.

METHODS:

A population-based cohort study based on the Taiwan National Health Insurance Research Database was conducted. From all potential participants aged 50 years or more, a total of 58 570 matched (1:1) pairs of HCV-infected patients and non-HCV-infected patients were included. Each subject was individually tracked from 1997 to 2009 to identify incident cases of dementia (onset in 1999 or later). Cox proportional hazards regressions were employed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between HCV infection and dementia.

RESULTS:

There were 2989 dementia cases from the HCV-infected cohort during the follow-up period of 533 861.1 person-years; the overall incidence rates of dementia differed from the non-HCV cohort (56.0 vs. 47.7 cases per 10 000 person-years, P < 0.05). The adjusted HR for dementia was 1.36 (95% CI 1.27-1.42) for HCV-infected patients after adjusting for alcohol-related disease, liver cirrhosis, hepatic encephalopathy and hepatocellular carcinoma.

CONCLUSIONS:

HCV infection may increase the risk for dementia. Further mechanistic research is needed.

Experimental drug may work against hepatitis C

(HealthDay)—An experimental therapy for hepatitis C—a "silent killer" linked to liver cancer and cirrhosis—has shown promise in tamping down virus levels in early trials."

Interferon-Free Therapy For Hepatitis C May Become A Reality

A new exploratory agent has been tested in the treatment of the hepatitis C virus infection (HCV), allowing patients to avoid the current interferon treatment that comes with harsh side effects. The drug is sofosbuvir, an oral nucleotide inhibitor of the viral polymerase. MNT

Valine, a branched-chain amino Acid, reduced HCV viral load and led to eradication of HCV by interferon therapy in a decompensated cirrhotic patient.

A decreased serum level of branched-chain amino acid (BCAA) is a distinctive metabolic disorder in patients with liver cirrhosis. Recently, BCAA has been reported to exert various pharmacological activities, and valine, which is a BCAA, has been shown to affect lipid metabolism and the immune system in in vivo experiments. However, the clinical impact of valine supplementation on viral hepatitis C virus (HCV) load has never been reported. Here, we first describe a case of HCV-related advanced liver cirrhosis that was treated by an oral valine agent. The administration of valine resulted in an improvement of fatigue and a reduction in hepatic fibrosis indexes as well as serum α-fetoprotein level. Furthermore, a marked reduction in HCV RNA levels was seen after valine treatment. The patient was then treated by interferon β, resulting in the successful eradication of chronic HCV infection. Thus, valine may be involved in the reduction of HCV viral load and could support a sustained virologic response to interferon therapy.

Hepatitis C Related Nervous System Disorders

Chronic infection with hepatitis C virus (HCV) is associated with a wide spectrum of extrahepatic manifestations, affecting different organ systems. Neurological complications occur in a large number of patients and range from peripheral neuropathy to cognitive impairment. Pathogenetic mechanisms responsible for nervous system dysfunction are mainly related to the upregulation of the host immune response with production of autoantibodies, immune complexes, and cryoglobulins. Alternative mechanisms include possible extrahepatic replication of HCV in neural tissues and the effects of circulating inflammatory cytokines and chemokines.

Liver Cancer Could Be Due To Absence Of microrna MIR122

In this study,mice lacking the miR-122 gene developed fatty deposits in their livers, got hepatitis, and grew tumors that resembled hepatocellular carcinoma. These disease signs were accompanied by over-active cancer signalling pathways, and that the livers were full of inflammatory cells that produce tumor-generating molecules called cytokines, including two well-known to cancer researchers, IL-6 and TNF. MIR122 also regulates replication of the hepatitis C virus.

Dynamic oscillation of translation and stress granule formation mark the cellular response to virus infection.

Virus infection-induced global protein synthesis suppression is linked to assembly of stress granules (SGs), cytosolic aggregates of stalled translation preinitiation complexes. To study long-term stress responses, we developed an imaging approach for extended observation and analysis of SG dynamics during persistent hepatitis C virus (HCV) infection. In combination with type 1 interferon, HCV infection induces highly dynamic assembly/disassembly of cytoplasmic SGs, concomitant with phases of active and stalled translation, delayed cell division, and prolonged cell survival. Double-stranded RNA (dsRNA), independent of viral replication, is sufficient to trigger these oscillations. Translation initiation factor eIF2α phosphorylation by protein kinase R mediates SG formation and translation arrest. This is antagonized by the upregulation of GADD34, the regulatory subunit of protein phosphatase 1 dephosphorylating eIF2α. Stress response oscillation is a general mechanism to prevent long-lasting translation repression and a conserved host cell reaction to multiple RNA viruses, which HCV may exploit to establish persistence.

Fatigue Before, During and After Antiviral Therapy of Chronic Hepatitis C: Results from the Virahep-C Study.

Fatigue is the most frequent and often debilitating symptom of chronic hepatitis C. It is unclear whether successful therapy of hepatitis C leads to its clinical improvement. In the Virahep-C study, patients with hepatitis C virus (HCV) genotype 1 infection were treated with peginterferon alfa-2a and ribavirin for up to 48 weeks while undergoing assessment of viral kinetics and clinical symptoms. METHODS:Fatigue measurements were conducted, before, during and after therapy, as 'presence' (yes/no) and 'severity' (visual analogue scale: 0 to 100mm). The clinical, histologic and virologic features that correlated with the presence and degree of fatigue were assessed focusing upon changes associated with sustained virological response (SVR).RESULTS:At baseline, 52% (n= 401) participants reported having fatigue, which was more common in women than men (59% vs. 48%, p=0.02) and slightly more severe (30 vs. 22mm, p=0.056). Fatigue was frequent and worse in cirrhotics versus those with lesser fibrosis (66% vs. 49%; 34 vs. 24mm). Fatigue did not correlate with other parameters. The proportion of patients and median fatigue scores increased on treatment (52% to 78%; 25 to 40mm, p<0.0001) with higher fatigue noted amongst those who ultimately achieved SVR (p<0.0001). On achieving SVR, there was a significant decrease in both frequency and severity of fatigue compared to their baseline (53% to 33%; 27 to 13mm, both p<0.0001).CONCLUSION:Fatigue is common in patients with chronic hepatitis C but associated poorly with biochemical parameters. Sustained response is accompanied by substantial improvement of fatigue.

Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria.

The mammalian intestinal tract is colonized by trillions of beneficial commensal bacteria that are anatomically restricted to specific niches. However, the mechanisms that regulate anatomical containment remain unclear. Here, we show that interleukin-22 (IL-22)-producing innate lymphoid cells (ILCs) are present in intestinal tissues of healthy mammals. Depletion of ILCs resulted in peripheral dissemination of commensal bacteria and systemic inflammation, which was prevented by administration of IL-22. Disseminating bacteria were identified as Alcaligenes species originating from host lymphoid tissues. Alcaligenes was sufficient to promote systemic inflammation after ILC depletion in mice, and Alcaligenes-specific systemic immune responses were associated with Crohn's disease and progressive hepatitis C virus infection in patients. Collectively, these data indicate that ILCs regulate selective containment of lymphoid-resident bacteria to prevent systemic inflammation associated with chronic diseases.

Regulation of Neuronal Proapoptotic Potassium Currents by the Hepatitis C Virus Nonstructural Protein 5A

Apoptosis-enabling neuronal potassium efflux is mediated by an enhancement of K⁺ currents. In cortical neurons, increased currents are triggered by dual phosphorylation of Kv2.1 by Src and p38 at channel residues Y124 and S800. It was recently shown that a K⁺ current surge is also present in hepatocytes undergoing apoptosis, and that the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) could inhibit Kv2.1-mediated currents and block cell death. Here, we show that NS5A1b (from HCV genotype 1b) expression in rat neurons depresses delayed rectifier potassium currents, limits the magnitude of the K⁺ current surge following exposure to activated microglia, and is neuroprotective. In a non-neuronal recombinant expression system, cells expressing Kv2.1 mutated at residue Y124, but not S800 mutants, are insensitive to NS5A1b-mediated current inhibition. Accordingly, NS5A1b coexpression prevents phosphorylation of wild-type Kv2.1 by Src at Y124, but is unable to inhibit p38 phosphorylation of the channel at S800. The actions of the viral protein are genotype-selective, as NS5A1a does not depress neuronal potassium currents nor inhibit Src phosphorylation of Kv2.1. Our results indicate that NS5A1b limits K⁺ currents following injury, leading to increased neuronal viability. NS5A1b may thus serve as a model for a new generation of neuroprotective agents.

Intrinsically Unstructured Domain 3 of Hepatitis C Virus NS5A Forms a "Fuzzy Complex" with VAPB-MSP Domain Which Carries ALS-Causing Mutations.

Hepatitis C virus (HCV) affects nearly 200 million people worldwide and is a leading factor for serious chronic liver diseases. For replicating HCV genome, the membrane-associated replication machinery needs to be formed by both HCV non-structural proteins including NS5A and human host factors. Recently NS5A has been identified to bind ER-anchored human VAP proteins and consequently this interaction may serve as a novel target for design of anti-HCV drugs. So far no biophysical characterization of this interaction has been reported. Here, we dissected the 243-residue VAPB into 4 and 447-residue NS5A into 10 fragments, followed by CD and NMR characterization of their structural properties. Subsequently, binding interactions between these fragments have been extensively assessed by NMR HSQC titration which is very powerful in detecting even very weak binding. The studies lead to three important findings: 1). a "fuzzy complex" is formed between the intrinsically-unstructured third domain (D3) of NS5A and the well-structured MSP domain of VAPB, with an average dissociation constant (Kd) of ∼5 µM. 2). The binding-important residues on both NS5A-D3 and VAPB-MSP have been successfully mapped out, which provided experimental constraints for constructing the complex structure. In the complex, unstructured D3 binds to three surface pockets on one side of the MSP structure. Interestingly, two ALS-causing mutations T46I and P56S are also located on the D3-MSP interface. Moreover, NS5A-D3, FFAT-containing proteins and EphA4 appear to have overlapped binding interfaces on the MSP domain. 3). NS5A-D3 has been experimentally confirmed to competes with EphA4 in binding to the MSP domain, and T46I mutation of MSP dramatically abolishes its binding ability to D3. Our study not only provides essential foundation for further deciphering structure and function of the HCV replication machinery, but may also shed light on rationalizing a recent observation that a chronic HCV patient surprisingly developed ALS-like syndrome.

Lipid metabolite profiling identifies desmosterol metabolism as a new antiviral target for hepatitis C virus.

Hepatitis C virus (HCV) infection has been clinically associated with serum lipid abnormalities, yet our understanding of the effects of HCV on host lipid metabolism and conversely the function of individual lipids in HCV replication remains incomplete. Using liquid chromatography-mass spectrometry metabolite profiling of the HCV JFH1 cell culture infection model, we identified a significant steady-state accumulation of desmosterol, an immediate precursor to cholesterol. Pharmacological inhibition or RNAi-mediated depletion of DHCR7 significantly reduced steady-state HCV protein expression and viral genomic RNA. Moreover, this effect was reversed when cultures were supplemented with exogenous desmosterol. Together, these observations suggest an intimate connection between HCV replication and desmosterol homeostasis and that the enzymes responsible for synthesis of desmosterol may be novel targets for antiviral design.

Infections Cause Many Cancers Globally

A new study published Online First in The Lancet Oncology reveals that from 7.5 million cancer deaths in 2008, about 1.5 million were due to infections that could have either been prevented or treated.