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Journal of Virology, February 2009, p. 1312-1319, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01890-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus Neuroinvasion: Identification of Infected Cells{triangledown}

Jeffrey Wilkinson,1 Marek Radkowski,2 and Tomasz Laskus1*

St. Joseph's Hospital and Medical Center, Phoenix, Arizona,1 Institute of Infectious Diseases, Warsaw Medical University, Warsaw, Poland2

Received 8 September 2008/ Accepted 7 November 2008

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.

* Corresponding author. Mailing address: St. Joseph's Hospital and Medical Center, 350 W. Thomas Rd., Phoenix, AZ 85013. Phone: (602) 406-3132. Fax: (602) 406-7172. E-mail: Tomasz.laskus{at}chw.edu

{triangledown} Published ahead of print on 19 November 2008.

Journal of Virology, February 2009, p. 1312-1319, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01890-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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