Hepatitis C Virus Neuroinvasion: Identification of Infected Cells

Abstract

Hepatitis C virus (HCV) infection often is associated with cognitive dysfunction and depression. HCV sequences and replicative forms were detected in autopsy brain tissue and cerebrospinal fluid from infected patients, suggesting direct neuroinvasion. However, the phenotype of cells harboring HCV in brain remains unclear. We studied autopsy brain tissue from 12 HCV-infected patients, 6 of whom were coinfected with human immunodeficiency virus. Cryostat sections of frontal cortex and subcortical white matter were stained with monoclonal antibodies specific for microglia/macrophages (CD68), oligodendrocytes (2,3-cyclic nucleotide 3-phosphodiesterase), astrocytes (glial fibrillary acidic protein [GFAP]), and neurons (neuronal-specific nuclear protein); separated by laser capture microscopy (LCM); and tested for the presence of positive-and negative-strand HCV RNA. Sections also were stained with antibodies to viral nonstructural protein 3 (NS3), separated by LCM, and phenotyped by real-time PCR. Finally, sections were double stained with antibodies specific for the cell phenotype and HCV NS3. HCV RNA was detected in CD68-positive cells in eight patients, and negative-strand HCV RNA, which is a viral replicative form, was found in three of these patients. HCV RNA also was found in astrocytes from three patients, but negative-strand RNA was not detected in these cells. In double immunostaining, 83 to 95% of cells positive for HCV NS3 also were CD68 positive, while 4 to 29% were GFAP positive. NS3-positive cells were negative for neuron and oligodendrocyte phenotypic markers. In conclusion, HCV infects brain microglia/macrophages and, to a lesser extent, astrocytes. Our findings could explain the biological basis of neurocognitive abnormalities in HCV infection.Patients with chronic hepatitis C virus (HCV) infection were reported to be more likely to manifest impairments in the quality of life, fatigue, and depression than patients with liver disease of other etiology (3,12,14,39). More recently, HCV infection was associated with cognitive dysfunction (11, 13). Importantly, Forton and colleagues, using proton magnetic resonance spectroscopy ( 1 H MRS), demonstrated elevations of choline/creatine ratios in basal ganglia and white matter in patients with mild hepatitis C disease that were not present in healthy volunteers or patients with hepatitis (9, 11). The presence of similar abnormalities consisting of increased choline and reduced N-acetyl aspartate levels among HCV-positive patients relative to those of controls has since been reported by other researchers (25, 41). The 1 H MRS changes in HCV infection are different from those seen in hepatic encephalopathy, where the choline ratios are depressed (40), but are similar to those found in patients with human immunodeficiency virus (HIV) infection (24, 26). Additional evidence for the biological basis of HCV-related cognitive dysfunction is provided by a recent report showing differences in gene expression patterns between brain tissue from HCV-positive and HCV-nega...

Hepatitis C virus and neurological damage

“…Based on the relatively low HCV RNA content in brain to the liver, detection of HCV antigen in the brain is extremely challenging, and existing imaging methodologies are not sensitive enough to detect the cells of CNS that are infected by the virus [29] . Prior studies have shown the presence of HCV RNA in microglia and astrocytes that were also isolated by laser capture microdissection [36,37] . Another study has shown that two independently derived brain endothelial cell lines (hCMEC/D3 and HBMEC) facilitate the entry and replication of the virus.…”

Systemic abnormalities in liver disease

“…Furthermore, fatigue or depression is found in many patients with chronic HCV infection, with incidences of about 50% and 35%, respectively [173][174][175] . These neurocognitive dysfunctions have been characterized epidemiologically or pathophysiologically in chronic HCV infection [166,167,176] , and may be explained by the neuroinvasion of HCV, because HCV has been reported to be found in monocytes/microglia of the central nervous system [176,177] . However, antiviral treatment with interferon, particularly interferon-α, is known to exacerbate depression [178] .…”

Expression of MicroRNA miR-122 Facilitates an Efficient Replication in Nonhepatic Cells upon Infection with Hepatitis C Virus

“…Mixed cryoglobulinemia is the most-well-characterized HCV-associated disease and is curable by viral clearance through antiviral therapies (6). Although replication of HCV RNA in peripheral blood mononuclear cells (PBMCs) and neuronal cells at a low level was suggested (64), the biological significance of the extrahepatic replication of HCV, particularly in the development of EHMs, is not well understood.…”