Monday, May 21, 2012

Hepatitis C Virus and the Brain

From Journal of Viral Hepatitis

Hepatitis C Virus and the Brain

N. F. Fletcher and J. A. McKeating

Authors and Disclosures
N. F. Fletcher and J. A. McKeating
Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK
Correspondence
Nicola F. Fletcher, Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK. E-mail: n.fletcher@bham.ac.uk

Posted: 05/21/2012; J Viral Hepat. 2012;19(5):301-306. © 2012 Blackwell Publishing

Abstract and Introduction
Abstract
Hepatitis C virus (HCV) is an enveloped, positive-strand RNA virus of the family Flaviviridae that primarily infects hepatocytes, causing acute and chronic liver disease. HCV is also associated with a variety of extrahepatic symptoms including central nervous system (CNS) abnormalities, cognitive dysfunction, fatigue and depression. These symptoms do not correlate with the severity of liver disease and are independent of hepatic encephalopathy. HCV RNA has been associated with CNS tissue, and reports of viral sequence diversity between brain and liver tissue suggest independent viral evolution in the CNS and liver. This review will explore the data supporting HCV infection of the CNS and how this fits into our current understanding of HCV pathogenesis.

Introduction
Hepatitis C virus (HCV) is a positive stranded virus, which is classified in its own genus, Hepacivirus, within the Flaviviridae family. Approximately 170 million individuals are infected with HCV worldwide, and infection leads to a progressive liver disease including hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC).[1] HCV is a leading cause for liver transplantation, and the number of patients requiring transplantation for chronic hepatitis C is increasing. HCV infects the newly transplanted liver in all cases, resulting in a more rapidly progressive disease.[2] HCV re-infection of the allograft is frequently associated with a shift in the viral quasispecies, leading several authors to suggest that extra-hepatic sites of HCV replication exist. Monitoring the HCV quasispecies in the plasma at the time of transplantation and identifying infecting strain(s) have led several authors to conclude that up to 4% of circulating virions are of extra-hepatic origin.[3-5]

Hepatocytes represent the major target for infection; however, HCV RNA has been detected in peripheral blood mononuclear cells, cerebrospinal fluid and the brain of chronically infected patients with neuropathological abnormalities.[6–8] Fatigue is the most commonly reported neurological symptom, with between 65% and 80% of chronically infected patients complaining of fatigue that is independent of liver dysfunction.[9,10] However, more recent studies using in vivo proton magnetic resonance spectroscopy demonstrate altered brain metabolism and cognitive dysfunction in HCV-infected patients without cirrhosis.[11,12] HCV-infected subjects perform significantly worse on various neuropsychological tasks than patients with liver disease of other causes.[11,13] Recent research efforts have investigated whether these abnormalities result from direct infection of the CNS or peripheral disease.

HCV RNA Association With Brain Tissue
The majority of reports supporting HCV in the CNS have used PCR-based approaches to detect viral genomes in brain tissue and cerebral spinal fluid (CSF).[14–21] However, the detection of viral RNA alone does not reflect active sites of replication and may simply represent viral carriage from the periphery. More recently, several authors have reported negative-strand HCV RNA, a replicative intermediate, in the CNS suggesting viral replication.[15,16,22] However, many studies include small numbers of patients, making it difficult to ascertain the frequency of HCV in brain tissue. A recent study quantified the levels of HCV RNA in multiple samples from the brain and liver of HCV-infected patients,[19] demonstrating between 1000 and 10 000-fold lower amounts of HCV RNA in brain tissue compared with liver, consistent with mild neuropathologies observed in HCV-infected patients. In summary, care is needed when interpreting the physiological relevance of HCV RNA genomes in brain tissue, where viral RNA could be a result of blood contamination and not direct evidence of viral replication.

There is some evidence of genetic diversity between viral strains isolated from brain tissue, PBMC, serum and liver biopsies from the same patient; Radkowski et al. observed that HCV NS3 sequences isolated from a variety of brain regions were similar to those isolated from lymph nodes but differed from serum-derived virus, suggesting independent viral evolution in the brain.[15] This study failed to detect negative-strand HCV RNA in the serum, leading the authors to conclude that viral sequences detected in the brain were not a result of blood contamination.[15] Similarly, variability in the HCV internal ribosomal entry site (IRES) was reported in brain tissue from two HCV-infected patients, compared with liver sequences.[20] More recently, a study of 13 HCV-infected patients, of which four had detectable HCV signals in brain tissue, used single nucleotide polymorphism analysis to identify a brain-specific mutation that constituted approximately 10% of HCV sequences in the cerebellum and medulla, whereas this mutation was undetectable in the liver and plasma of the same patients.[19] Taken together, these studies strengthen the evidence that HCV may replicate in the brain, raising questions on which cell types within the CNS support HCV infection.

HCV Infection is Associated With Immune Responses in the Brain
Recent studies have suggested that HCV infection is associated with inflammatory responses in the brain. The brain metabolites choline, creatine and inositol were significantly increased in HCV-infected patients compared with healthy controls,[23,24] yet those patients with low levels of fatigue had higher levels of choline than those with severe fatigue. Nevertheless, these results suggest activation of microglia and possibly astrocytes in HCV-infected patients with fatigue.[24] A recent study of treatment-naïve subjects with mild chronic HCV infection revealed microglial and brain macrophage activation using a combination of proton magnetic resonance spectroscopy and positron emission tomography (PET) with a ligand for neuroinflammation, which was not observed in HCV seronegative subjects.[25] This immune activation was associated with HCV viraemia and altered cerebral metabolism, demonstrating altered basal ganglia myoinositol/creatinine and choline/creatine ratios in HCV-infected patients,[25] putative biomarkers of glial cell inflammation and activation.[23,26] This observation was reported in a group of 22 HCV-infected patients, of which 15 were treated with pegylated interferon and ribavirin, and seven were untreated HCV-positive controls.[27] In the treated group, the patients who responded to therapy had lower cerebral metabolite measurements (reductions in choline and myoinositol) than non-responders or untreated controls, and the reduction in metabolites associated with improved neurocognitive performance.[27] A further study of postmortem tissue demonstrated that brain tissue from HCV-infected subjects expressed significantly increased levels of proinflammatory cytokines IL-1, TNF-α, IL-12, and IL-18,[28] which could explain glial cell activation reported in several studies. Astrogliosis and demyelination were reported in rare cases of HCV infection with severe neuropathology;[17,28,29] however, this is not observed in the majority of patients. These results demonstrate that higher viral load and lower neurocognitive performance correlate with increased immune activation in the CNS of HCV-infected individuals; further large-scale studies are required to ascertain the extent to which this phenomenon occurs in chronic hepatitis C.

Identifying HCV Permissive Brain Cells
Visualizing HCV antigen-expressing hepatocytes in the liver has been technically challenging, most likely reflecting the low viral burden at a cellular level.[30,31] Given the low levels of HCV RNA reported in the brain, it will be technically challenging to identify viral antigen-expressing cells. Previous studies have reported the presence of viral RNA in microglia and astrocytes isolated using laser capture microdissection.[22,32] However, recent immunohistochemical studies show that astrocytes and microglia do not express the viral receptors required for HCV entry.[33,34] A recent screen of neural cells for their ability to support HCV infection demonstrated that two independent neuroepithelioma cell lines support HCV entry and replication, and both lines expressed all of the cellular molecules required for virus entry: scavenger receptor B-I (SR-BI); tetraspanin CD81 and tight junction proteins claudin-1 and occludin.[33,35] Neuroepithelioma cell lines supported high level entry of retroviral particles pseudotyped with HCV glycoproteins in a receptor-dependent manner.[33,35] These observations contrast with a recent report showing limited evidence for HCV entry or replication in various immune cell types.[36] These studies were the first to demonstrate productive HCV entry in non-hepatic cells that were not engineered to express the viral receptors.[37] However, these results are unlikely to correspond to HCV infection of neurons in vivo. Neuroepitheliomas are peripheral tumours derived from neural crest-derived neuroepithelium, which represent a less differentiated aspect of the neural lineage[38] and are unlikely to correspond to any cell type in normal CNS. Moreover, in the same study, neuronal cell lines failed to support HCV entry.[33] However, the expression of SR-BI, CD81, claudin-1 and occludin in neuroepithelioma cells demonstrates that HCV receptor expression is not exclusive to hepatocytes and infection may not be solely restricted to the liver.

A recent study reported that brain microvascular endothelial cells (BMEC), the major component of the blood/brain barrier, support HCV infection in vitro.[39] Two independently derived brain microvascular endothelial cell lines, hCMEC/D3 and HBMEC, expressed all of the HCV entry factors and supported HCV pseudoparticle entry and HCVcc infection. Furthermore, immunochemical staining of human brain sections revealed that microvascular endothelium express all four receptors required for HCV entry. Notably, SR-BI expression was restricted to brain microvascular endothelium,[33] suggesting that HCV tropism for the brain may be restricted to these cells. HCVpp expressing diverse glycoproteins infected BMEC, and entry was neutralized by anti-receptor and anti-HCV E2 antibodies, demonstrating a common entry pathway to that reported for hepatocytes.[33] HCVpp infection was restricted to brain-derived endothelial cells, with endothelial cells isolated from liver sinusoids or umbilical vein endothelium failing to support HCV infection. Importantly, BMEC was permissive for cell culture-derived HCV (HCVcc), showing a spreading infection and release of particles that were infectious for Huh-7 hepatoma cells. Viral infection persisted in Huh-7 cells, whereas infection declined in BMEC after 120 h and was associated with cytopathic effects, suggesting an acute lytic infection compared with the chronic infection observed in hepatoma cells. Apoptosis was observed in BMEC cultures infected with HCV, and endothelial barrier activity reduced following infection; this was reversed by the addition of HCV-positive patient serum.[39]

Endothelial cells of the blood/brain barrier (BBB) differ from endothelial cells elsewhere in the body in a number of respects. Tight junctions in brain endothelium are more complex than those of peripheral endothelium, leading to epithelial-like polarity.[40] These tight junctions exclude the passage of large, water-soluble substances into the brain from the bloodstream. Passage of large and lipophilic substances into the brain across the BBB typically occurs via receptor-mediated endocytosis, and some substances are transported via transport proteins such as the GLUT-1 glucose transporter.[40] Brain microvascular endothelial cells are surrounded by astrocyte end feet and pericytes that help maintain barrier integrity[40] (Fig. 1). Our in vitro studies showing HCV-infected BMEC apoptosis suggest that HCV may disrupt BBB integrity in vivo. This could allow the influx of inflammatory cytokines and virus to the brain parenchyma, which could give rise to the relatively mild neurological symptoms observed in patients. HCV replication and assembly of infectious particles in BMEC suggests that the brain may contribute to HCV pathogenesis via direct viral infection of the BBB (Fig. 2), which raises questions on the potential efficacy of therapies currently in development, such as protease and polymerase inhibitors,[41] as they may achieve low drug levels in the brain because of the expression of efficient drug efflux pumps at the BBB such as P-glycoprotein. There may be difficulties in delivering these drugs to the CNS, similar to those reported in HIV infection where reservoirs of infection develop in immune-privileged sites such as the brain.[42]



Figure 1.
The blood/brain barrier (BBB) in vivo. The BBB is formed by brain microvascular endothelial cells, which polarize and form tight junctions, thereby limiting the passage of substances into the central nervous system (CNS). Endothelial cells are surrounded by a basal lamina and astrocytic endfeet, which secrete factors that help to maintain the endothelial cell phenotype. Pericytes also surround the endothelium, and recent evidence suggests that these cells contribute to the maintenance of barrier function. These cells, together with surrounding neurons, form a 'neurovascular unit', which function to regulate cerebral blood flow [40].




Figure 2.
Proposed neuropathogenesis of HCV infection. The chronically infected liver produces approximately 1012 viral particles per day, which are released into the bloodstream and encounter brain microvascular endothelial cells of the BBB. Brain microvascular endothelial cells express all of the receptors required for viral entry, together with LDL-R and Apolipoprotein E. Direct viral infection of BBB endothelial cells may occur, resulting in apoptosis and BBB breakdown that could allow entry of inflammatory cytokines, viral particles and other neurotoxic substances that may potentiate neurological symptoms and activate microglial cells and astrocytes. Infection of brain microvascular endothelium is likely to impact upon astrocyte homoeostasis, and some studies have suggested that HCV infects astrocytes. Productive infection of brain microvascular endothelium and the release of infectious viral particles could contribute to viral persistence.

HIV is a Frequent Co-pathogen With HCV
Owing to similar modes of transmission, an estimated 30% of HIV positive individuals are co-infected with HCV in the USA and Europe.[43] In high risk groups, the rate of co-infection rises and HCV is found in 50–70% of HIV-infected intravenous drug users.[43] HCV co-infection with HIV leads to accelerated hepatic fibrosis progression and increased rates of cirrhosis and liver failure compared with HCV mono-infected individuals.[44] HIV is known to enter the brain early after infection and can infect microglia, perivascular macrophages and astrocytes (for reviews, see [45,46] HIV infection can cause severe HIV-associated dementia in untreated individuals; however, even in the setting of optimally treated HIV infection, brain replication persists and gives rise to minor cognitive motor disorder (MCMD) in a significant number of patients, because of poor brain penetration of therapies across the BBB.[46] HCV-HIV co-infected individuals perform worse in neurocognitive tests compared with HIV-monoinfected individuals[47] and are more likely to be diagnosed with HIV-associated dementia.[47] A study of co-infected individuals performed both pre- and postmortem suggested an association between poorly controlled HIV infection and the presence of HCV in the brain, and patients with detectable HCV in the brain had higher plasma HIV viral loads.[18] Although the study only assessed small numbers of patients, there was a trend towards increased levels of cognitive deficits in co-infected patients with detectable brain HCV, compared with mono-infected patients or those with HCV restricted to systemic locations.[18] Further studies of co-infected patients has suggested that successful HIV therapy may reduce the levels of increased cognitive impairment attributed to HCV infection, although correlation of cognitive impairment with detectable levels of virus in the brain was not investigated.[48–50] White matter abnormalities were recently reported in co-infected patients,[51,52] suggesting neuropathological processes directly related to the presence of HCV in the brain. Furthermore, plasma cytokine IL-6, IL-16 and MIP-1β levels in co-infected patients associate with neurocognitive abnormalities,[53] suggesting that the interplay of HIV, HCV and inflammatory host responses may contribute to neuropathology in co-infected individuals. These clinical and translational reports warrant further studies to determine the interactions of these viruses in the central nervous system, and the mechanisms by which they contribute to neural dysfunction in infected individuals.

Conclusions
Hepatitis C is a member of the Flaviviridae, whose members include a number of neurovirulent viruses, including Japanese encephalitis virus, West Nile virus and Tick-borne encephalitis virus.[54] Neurological symptoms associated with HCV infection have been reported many times; however, it has been unclear whether these symptoms are a function of liver disease, peripheral inflammation or direct infection of the CNS. The detection of HCV RNA in brain tissue, together with evidence to suggest independent viral evolution within the CNS, has suggested that the neurological symptoms reported in patients may result from direct infection of the brain. Recent advances in the tools available to study HCV have allowed researchers to address the question of whether HCV replicates in brain-derived cells. The recent observation that HCV can replicate in brain endothelial cells, and that neuroinflammation is a feature of HCV infection, may provide a mechanism for the neurological symptoms observed in a significant number of infected patients.

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