Chapter 21 : Hepatitis C Virus: Variability, Extrahepatic Replication, and Neuroinvasion

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Recent studies focusing on Hepatitis C virus (HCV) survival strategies revealed that viral proteins may interfere with pathways of retinoid-acid-inducible gene I and Toll-like receptor 3, which constitute two major pathways of host defense triggered by viral nucleic acids. In particular, HCV seems to interfere at several different points with interferon (IFN) and IFN-stimulated gene signaling. A powerful strategy employed by the virus is genetic variability resulting in the constant and dynamic development of variants capable of avoiding eradication by host defenses. Several studies have reported that transmission of infection may be limited to a few variants present within the quasispecies population. Thus, viral populations found in children infected at birth were found to be more homogeneous than those in mothers. HCV infection is common among HIV-positive patients, as the two pathogens share similar routes of transmission. HCV is a positive-strand RNA virus, which replicates through negative-strand RNA, the presence of which could be regarded as direct evidence of ongoing replication. HCV RNA-negative strand was detected only in a minority of cases; however, it is likely that the strand-specific assays are not sensitive enough to detect low-level extra hepatic replication. Infected macrophages and microglia cells could release proinflammatory cytokines, such as tumor necrosis factor (TNF)- α, interleukin-1 (IL-1), and IL-6, neurotoxins such as nitric oxide, and viral proteins, which could induce alteration in brain function leading in turn to neurocognitive dysfunction and depression.

Citation: Radkowski M, Nasseri J, Laskus T. 2009. Hepatitis C Virus: Variability, Extrahepatic Replication, and Neuroinvasion, p 295-311. In Goodkin K, Shapshak P, Verma A (ed), The Spectrum of Neuro-AIDS Disorders. ASM Press, Washington, DC. doi: 10.1128/9781555815691.ch21
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A working hypothesis regarding the effects of HCV on brain. HCV can infect PBMC, particularly macrophages, and this process is facilitated by concomitant HIV coinfection. Infected macrophages could cross the blood-brain barrier. Following the entry into the brain, infected macrophages release proinflammatory cytokines, which could induce alteration in brain function leading in turn to neurocognitive dysfunction. HCV infection may be also associated with oxidative stress, which could be due to release of reactive oxygen species by macrophages or to the direct effect of viral proteins on mitochondria.

Citation: Radkowski M, Nasseri J, Laskus T. 2009. Hepatitis C Virus: Variability, Extrahepatic Replication, and Neuroinvasion, p 295-311. In Goodkin K, Shapshak P, Verma A (ed), The Spectrum of Neuro-AIDS Disorders. ASM Press, Washington, DC. doi: 10.1128/9781555815691.ch21
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1. Adair, D.,, M. Radkowski,, J. Jablonska,, A. Pawelczyk,, J. Wilkinson,, J. Rakela, and, T. Laskus. 2005. Differential display analysis of gene expression in brain from hepatitis C infected patients. AIDS 3 (Suppl.): S145S150.
2. Adair, D.,, J. Wilkinson,, A. Scheck,, M. Radkowski,, J. Rakela, and, T. Laskus. 2004. Differential display and micro-array analysis show differentially expressed genes in central nervous system in HCV infected patients and laser capture microscopy points to brain microglia as cells harboring HCV. Hepatology 40: 433A.
3. Alter, M. J. 1999. Hepatitis C virus infection in the United States. J. Hepatol. 31: 8891.
4. Alter, M. J.,, D. Kruszon-Moran,, O. V. Nainan,, G. M. McQuillan,, F. Gao,, L. A. Moyer,, R. A. Kaslow, and, H. S. Margolis. 1999. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N. Engl. J. Med. 341: 556562.
5. Alter, M. J.,, H. S. Margolis,, K. Krawczynski,, F. N. Judson,, A. Mares,, W. J. Alexander,, P. Y. Hu,, J. K. Miller,, M. A. Gerber,, R. E. Sampliner,, E. L. Meeks,, M. J. Beach, et al. 1992. The natural history of community-acquired hepatitis C in the United States. N. Engl. J. Med. 327: 18991905.
6. Althausen, S.,, T. Mengesdorf,, G. Mies,, L. Olah,, A. C. Nairn,, C. G. Proud, and, W. Paschen. 2001. Changes in the phosphorylation of initiation factor eIF-2alpha, elongation factor eEF-2 and p70 S6 kinase after transient focal cerebral ischaemia in mice. J. Neurochem. 78: 779787.
7. Amedee, A. M.,, N. Lacour,, J. L. Gierman,, L. N. Martin,, J. E. Clements,, R. Bohm, Jr.,, R. M. Harrison, and, M. Murphey-Corb. 1995. Genotypic selection of simian immunodeficiency virus in macaque infants infected transplacentally. J. Virol. 69: 79827990.
8. Arenas, J. I.,, J. F. Gallegos-Orozco,, T. Laskus,, J. Wilkinson,, A. Khatib,, C. Fasola,, D. Adair,, M. Radkowski,, K. V. Kibler,, M. Nowicki,, D. Douglas,, J. Williams,, G. Netto,, D. Mulligan,, G. Klintmalm,, J. Rakela, and, H. E. Vargas. 2004. Hepatitis C virus quasispecies dynamics predict progression of fibrosis after liver transplantation. J. Infect. Dis. 189: 20372046.
9. Aschner, M. 1998. Immune and inflammatory responses in the CNS: modulation by astrocytes. Toxicol. Lett. 102–103: 283287.
10. Auffermann-Gretzinger, S.,, E. B. Keeffe, and, S. Levy. 2001. Impaired dendritic cell maturation in patients with chronic, but not resolved, hepatitis C virus infection. Blood 97: 31713176.
11. Azzari, C.,, M. Resti,, M. Moriondo,, R. Ferrari,, P. Lionetti, and, A. Vierucci. 2000. Vertical transmission of HCV is related to maternal peripheral blood mononuclear cell infection. Blood 96: 20452048.
12. Bain, C.,, A. Fatmi,, F. Zoulim,, J. P. Zarski,, C. Trepo, and, G. Inchauspe. 2001. Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection. Gastroenterology 120: 512524.
13. Barkhuizen, A.,, H. R. Rosen,, S. Wolf,, K. Flora,, K. Benner, and, R. M. Bennett. 1999. Musculoskeletal pain and fatigue are associated with chronic hepatitis C: a report of 239 hepatology clinic patients. Am. J. Gastroenterol. 94: 13551360.
14. Bassett, S. E.,, D. L. Thomas,, K. M. Brasky, and, R. E. Lanford. 1999. Viral persistence, antibody to E1 and E2, and hypervariable region 1 sequence stability in hepatitis C virus-inoculated chimpanzees. J. Virol. 73: 11181126.
15. Becker, S.,, J. Quay, and, J. Soukup. 1991. Cytokine (tumor necrosis factor, IL-6, and IL-8) production by respiratory syncytial virus-infected human alveolar macrophages. J. Immunol. 147: 43074312.
16. Beld, M.,, M. Penning,, V. Lukashov,, M. McMorrow,, M. Roos,, N. Pakker,, A. van den Hoek, and, J. Goudsmit. 1998. Evidence that both HIV and HIV-induced immunodeficiency enhance HCV replication among HCV seroconverters. Virology 244: 504512.
17. Blackard, J. T.,, L. Smeaton,, Y. Hiasa,, N. Horiike,, M. Onji,, D. J. Jamieson,, I. Rodriguez,, K. H. Mayer, and, R. T. Chung. 2005. Detection of hepatitis C virus (HCV) in serum and peripheral-blood mononuclear cells from HCV-monoinfected and HIV/HCV-coinfected persons. J. Infect. Dis. 192: 258265.
18. Blass, J. P. 2001. Brain metabolism and brain disease: is metabolic deficiency the proximate cause of Alzheimer dementia? J. Neurosci. Res. 66: 851856.
19. Bocharov, G.,, B. Ludewig,, A. Bertoletti,, P. Klenerman,, T. Junt,, P. Krebs,, T. Luzyanina,, C. Fraser, and, R. M. Anderson. 2004. Underwhelming the immune response: effect of slow virus growth on CD8+-T-lymphocyte responses. J. Virol. 78: 22472254.
20. Bolay, H.,, F. Soylemezoglu,, G. Nurlu,, S. Tuncer, and, K. Varli. 1996. PCR detected hepatitis C virus genome in the brain of a case with progressive encephalomyelitis with rigidity. Clin. Neurol. Neurosurg. 98: 305308.
21. Bonkovsky, H. L.,, J. M. Woolley, et al. 1999. Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. Hepatology 29: 264270.
22. Botarelli, P.,, M. R. Brunetto,, M. A. Minutello,, P. Calvo,, D. Unutmaz,, A. J. Weiner,, Q. L. Choo,, J. R. Shuster,, G. Kuo,, F. Bonino, et al. 1993. T-lymphocyte response to hepatitis C virus in different clinical courses of infection. Gastroenterology 104: 580587.
23. Bronowicki, J. P.,, M. A. Loriot,, V. Thiers,, Y. Grignon,, A. L. Zignego, and, C. Brechot. 1998. Hepatitis C virus persistence in human hematopoietic cells injected into SCID mice. Hepatology 28: 211218.
24. Bukh, J.,, R. H. Purcell, and, R. H. Miller. 1992. Sequence analysis of the 5′ noncoding region of hepatitis C virus. Proc. Natl. Acad. Sci. USA 89: 49424946.
25. Buratti, E.,, M. Gerotto,, P. Pontisso,, A. Alberti,, S. G. Tisminetzky, and, F. E. Baralle. 1997. In vivo translational efficiency of different hepatitis C virus 5′-UTRs. FEBS Lett. 411: 275280.
26. Capuron, L.,, and R. Dantzer. 2003. Cytokines and depression: the need for a new paradigm. Brain Behav. Immun. 17 (Suppl. 1): S119S124.
27. Castillo, I.,, M. Pardo,, J. Bartolome,, N. Ortiz-Movilla,, E. Rodriguez-Inigo,, S. de Lucas,, C. Salas,, J. A. Jimenez-Heffernan,, A. Perez-Mota,, J. Graus,, J. M. Lopez-Alcorocho, and, V. Carreno. 2004. Occult hepatitis C virus infection in patients in whom the etiology of persistently abnormal results of liver-function tests is unknown. J. Infect. Dis. 189: 714.
28. Caussin-Schwemling, C.,, C. Schmitt, and, F. Stoll-Keller. 2001. Study of the infection of human blood derived monocyte/macrophages with hepatitis C virus in vitro. J. Med. Virol. 65: 1422.
29. Cerino, A.,, and M. U. Mondelli. 1991. Identification of an immunodominant B cell epitope on the hepatitis C virus nonstructural region defined by human monoclonal antibodies. J. Immunol. 147: 26922696.
30. Chen, M.,, M. Sallberg,, A. Sonnerborg,, O. Weiland,, L. Mattsson,, L. Jin,, A. Birkett,, D. Peterson, and, D. R. Milich. 1999. Limited humoral immunity in hepatitis C virus infection. Gastroenterology 116: 135143.
31. Cherner, M.,, S. Letendre,, R. K. Heaton,, J. Durelle,, J. Marquie-Beck,, B. Gragg, and, I. Grant. 2005. Hepatitis C augments cognitive deficits associated with HIV infection and methamphetamine. Neurology 64: 13431347.
32. Choo, Q. L.,, G. Kuo,, R. Ralston,, A. Weiner,, D. Chien,, G. Van Nest,, J. Han,, K. Berger,, K. Thudium,, C. Kuo, et al. 1994. Vaccination of chimpanzees against infection by the hepatitis C virus. Proc. Natl. Acad. Sci. USA 91: 12941298.
33. Choo, Q. L.,, G. Kuo,, A. J. Weiner,, L. R. Overby,, D. W. Bradley, and, M. Houghton. 1989. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244: 359362.
34. Choo, Q. L.,, K. H. Richman,, J. H. Han,, K. Berger,, C. Lee,, C. Dong,, C. Gallegos,, D. Coit,, R. Medina-Selby,, P. J. Barr,, A. J. Weiner,, D. W. Bradley,, G. Kuo, and, M. Houghton. 1991. Genetic organization and diversity of the hepatitis C virus. Proc. Natl. Acad. Sci. USA 88: 24512455.
35. Coffin, C. S.,, and T. I. Michalak. 1999. Persistence of infectious hepadnavirus in the offspring of woodchuck mothers recovered from viral hepatitis. J. Clin. Investig. 104: 203212.
36. Collier, A. J.,, S. Tang, and, R. M. Elliott. 1998. Translation efficiencies of the 5′ untranslated region from representatives of the six major genotypes of hepatitis C virus using a novel bicistronic reporter assay system. J. Gen. Virol. 79: 23592366.
37. Crawford, D. R.,, Y. Wang,, G. P. Schools,, J. Kochheiser, and, K. J. Davies. 1997. Down-regulation of mammalian mitochondrial RNAs during oxidative stress. Free Radic. Biol. Med. 22: 551559.
38. Daar, E. S.,, H. Lynn,, S. Donfield,, E. Gomperts,, M. W. Hilgartner,, W. K. Hoots,, D. Chernoff,, S. Arkin,, W. Y. Wong, and, C. A. Winkler. 2001. Relation between HIV-1 and hepatitis C viral load in patients with hemophilia. J. Acquir. Immune Defic. Syndr. 26: 466472.
39. Davis, E. J.,, T. D. Foster, and, W. E. Thomas. 1994. Cellular forms and functions of brain microglia. Brain Res. Bull. 34: 7378.
40. De Luca, A.,, R. Bugarini,, A. C. Lepri,, M. Puoti,, E. Girardi,, A. Antinori,, A. Poggio,, G. Pagano,, G. Tositti,, G. Cadeo,, A. Macor,, M. Toti, and, A. D’Arminio Monforte. 2002. Coinfection with hepatitis viruses and outcome of initial antiretroviral regimens in previously naive HIV-infected subjects. Arch. Intern. Med. 162: 21252132.
41. Desjardins, P.,, M. Belanger, and, R. F. Butterworth. 2001. Alterations in expression of genes coding for key astrocytic proteins in acute liver failure. J. Neurosci. Res. 66: 967971.
42. Dockter, J.,, C. F. Evans,, A. Tishon, and, M. B. Oldstone. 1996. Competitive selection in vivo by a cell for one variant over another: implications for RNA virus quasispecies in vivo. J. Virol. 70: 17991803.
43. Domingo, E.,, E. Martinez-Salas,, F. Sobrino,, J. C. de la Torre,, A. Portela,, J. Ortin,, C. Lopez-Galindez,, P. Perez-Brena,, N. Villanueva,, R. Najera, et al. 1985. The quasispecies (extremely heterogeneous) nature of viral RNA genome populations: biological relevance—a review. Gene 40: 18.
44. Dorrucci, M.,, P. Pezzotti,, A. N. Phillips,, A. C. Lepri,, G. Rezza, et al. 1995. Coinfection of hepatitis C virus with human immunodeficiency virus and progression to AIDS. J. Infect. Dis. 172: 15031508.
45. Ducoulombier, D.,, A. M. Roque-Afonso,, G. Di Liberto,, F. Penin,, R. Kara,, Y. Richard,, E. Dussaix, and, C. Feray. 2004. Frequent compartmentalization of hepatitis C virus variants in circulating B cells and monocytes. Hepatology 39: 817825.
46. Eckels, D. D.,, H. Wang,, T. H. Bian,, N. Tabatabai, and, J. C. Gill. 2000. Immunobiology of hepatitis C virus (HCV) infection: the role of CD4 T cells in HCV infection. Immunol. Rev. 174: 9097.
47. Eyster, M. E.,, H. J. Alter,, L. M. Aledort,, S. Quan,, A. Hatzakis, and, J. J. Goedert. 1991. Heterosexual co-transmission of hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Ann. Intern. Med. 115: 764768.
48. Eyster, M. E.,, L. S. Diamondstone,, J. M. Lien,, W. C. Ehmann,, S. Quan,, J. J. Goedert, et al. 1993. Natural history of hepatitis C virus infection in multitransfused hemophiliacs: effect of coinfection with human immunodeficiency virus. J. Acquir. Immune Defic. Syndr. 6: 60210.
49. Eyster, M. E.,, K. E. Sherman,, J. J. Goedert,, A. Katsoulidou,, A. Hatzakis, et al. 1999. Prevalence and changes in hepatitis C virus genotypes among multitransfused persons with hemophilia. J. Infect. Dis. 179: 10621069.
50. Farci, P.,, H. J. Alter,, S. Govindarajan,, D. C. Wong,, R. Engle,, R. R. Lesniewski,, I. K. Mushahwar,, S. M. Desai,, R. H. Miller,, N. Ogata, and, R. H. Purcell. 1992. Lack of protective immunity against reinfection with hepatitis C virus. Science 258: 135140.
51. Farci, P.,, H. J. Alter,, D. C. Wong,, R. H. Miller,, S. Govindarajan,, R. Engle,, M. Shapiro, and, R. H. Purcell. 1994. Prevention of hepatitis C virus infection in chimpanzees after antibody-mediated in vitro neutralization. Proc. Natl. Acad. Sci. USA 91: 77927796.
52. Farci, P.,, A. Shimoda,, A. Coiana,, G. Diaz,, G. Peddis,, J. C. Melpolder,, A. Strazzera,, D. Y. Chien,, S. J. Munoz,, A. Balestrieri,, R. H. Purcell, and, H. J. Alter. 2000. The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. Science 288: 339344.
53. Ferbeyre, G.,, V. Bourdeau, and, R. Cedergren. 1997. Does HIV tat protein also regulate genes of other viruses present in HIV infection? Trends Biochem. Sci. 22: 115116. (Letter.)
54. Ferrari, C.,, A. Valli,, L. Galati,, A. Penna,, P. Scaccaglia,, T. Giuberti,, C. Schianchi,, G. Missale,, M. G. Marin, and, F. Fiaccadori. 1994. T-cell response to structural and nonstructural hepatitis C virus antigens in persistent and self-limited hepatitis C virus infections. Hepatology 19: 286295.
55. Forns, X.,, J. Bukh,, R. H. Purcell, and, S. U. Emerson. 1997. How Escherichia coli can bias the results of molecular cloning: preferential selection of defective genomes of hepatitis C virus during the cloning procedure. Proc. Natl. Acad. Sci. USA 94: 1390913914.
56. Forns, X.,, R. Thimme,, S. Govindarajan,, S. U. Emerson,, R. H. Purcell,, F. V. Chisari, and, J. Bukh. 2000. Hepatitis C virus lacking the hypervariable region 1 of the second envelope protein is infectious and causes acute resolving or persistent infection in chimpanzees. Proc. Natl. Acad. Sci. USA 97: 1331813323.
57. Forton, D. M.,, J. M. Allsop,, J. Main,, G. R. Foster,, H. C. Thomas, and, S. D. Taylor-Robinson. 2001. Evidence for a cerebral effect of the hepatitis C virus. Lancet 358: 3839.
58. Forton, D. M.,, P. Karayiannis,, N. Mahmud,, S. D. Taylor-Robinson, and, H. C. Thomas. 2004. Identification of unique hepatitis C virus quasispecies in the central nervous system and comparative analysis of internal translational efficiency of brain, liver, and serum variants. J. Virol. 78: 51705183.
59. Forton, D. M.,, H. C. Thomas,, C. A. Murphy,, J. M. Allsop,, G. R. Foster,, J. Main,, K. A. Wesnes, and, S. D. Taylor-Robinson. 2002. Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology 35: 433439.
60. Foster, G. R. 1999. Hepatitis C virus infection: quality of life and side effects of treatment. J. Hepatol. 31: 250254.
61. Gale, M.,, Jr., and E. M. Foy. 2005. Evasion of intracellular host defence by hepatitis C virus. Nature 436: 939945.
62. Gallegos-Orozco, J. F.,, J. I. Arenas,, K. Kibler,, J. Wilkinson,, D. Adair,, M. Radkowski,, H. Vargas,, T. Laskus, and, J. Rakela. 2004. Translation efficiency of hepatitis C 5′-untranslated region variants developing in transfusion acquired infection and in post-transplant recurrent hepatitis. Hepatology 40: 688A.
63. Gane, E. J.,, B. C. Portmann,, N. V. Naoumov,, H. M. Smith,, J. A. Underhill,, P. T. Donaldson,, G. Maertens, and, R. Williams. 1996. Long-term outcome of hepatitis C infection after liver transplantation. N. Engl. J. Med. 334: 815820.
64. Garcia-Samaniego, J.,, V. Soriano,, J. Castilla,, R. Bravo,, A. Moreno,, J. Carbo,, A. Iniguez,, J. Gonzalez,, F. Munoz, et al. 1997. Influence of hepatitis C virus genotypes and HIV infection on histological severity of chronic hepatitis C. Am. J. Gastroenterol. 92: 11301134.
65. Gerlach, J. T.,, H. M. Diepolder,, M. C. Jung,, N. H. Gruener,, W. W. Schraut,, R. Zachoval,, R. Hoffmann,, C. A. Schirren,, T. Santantonio, and, G. R. Pape. 1999. Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C. Gastroenterology 117: 933941.
66. Goh, J.,, B. Coughlan,, J. Quinn,, J. C. O′Keane, and, J. Crowe. 1999. Fatigue does not correlate with the degree of hepatitis or the presence of autoimmune disorders in chronic hepatitis C infection. Eur. J. Gastroenterol. Hepatol. 11: 833838.
67. Gong, G.,, G. Waris,, R. Tanveer, and, A. Siddiqui. 2001. Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-kappa B. Proc. Natl. Acad. Sci. USA 98: 95999604.
68. Goswami, S.,, N. L. Sheets,, J. Zavadil,, B. K. Chauhan,, E. P. Bottinger,, V. N. Reddy,, M. Kantorow, and, A. Cvekl. 2003. Spectrum and range of oxidative stress responses of human lens epithelial cells to H2O2 insult. Investig. Ophthalmol. Vis. Sci. 44: 20842093.
69. Granovsky, M. O.,, H. L. Minkoff,, B. H. Tess,, D. Waters,, A. Hatzakis,, D. E. Devoid,, S. H. Landesman,, A. Rubinstein,, A. M. Di Bisceglie, and, J. J. Goedert. 1998. Hepatitis C virus infection in the mothers and infants cohort study. Pediatrics 102: 355359.
70. Gretch, D. R.,, S. J. Polyak,, J. J. Wilson,, R. L. Carithers, Jr.,, J. D. Perkins, and, L. Corey. 1996. Tracking hepatitis C virus quasispecies major and minor variants in symptomatic and asymptomatic liver transplant recipients. J. Virol. 70: 76227631.
71. Greub, G.,, B. Ledergerber,, M. Battegay,, P. Grob,, L. Perrin,, H. Furrer,, P. Burgisser,, P. Erb,, K. Boggian,, J. C. Piffaretti,, B. Hirschel,, P. Janin,, P. Francioli,, M. Flepp, and, A. Telenti. 2000. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet 356: 18001805.
72. Gruener, N. H.,, F. Lechner,, M. C. Jung,, H. Diepolder,, T. Gerlach,, G. Lauer,, B. Walker,, J. Sullivan,, R. Phillips,, G. R. Pape, and, P. Klenerman. 2001. Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. J. Virol. 75: 55505558.
73. Hanley, J. P.,, L. M. Jarvis,, J. Andrews,, R. Dennis,, R. Lee,, P. Simmonds,, J. Piris,, P. Hayes, and, C. A. Ludlam. 1996. Investigation of chronic hepatitis C infection in individuals with haemophilia: assessment of invasive and non-invasive methods. Br. J. Haematol. 94: 159165.
74. Heckmann, J. G.,, C. Kayser,, D. Heuss,, B. Manger,, H. E. Blum, and, B. Neundorfer. 1999. Neurological manifestations of chronic hepatitis C. J. Neurol. 246: 486491.
75. Herbein, G.,, and W. A. O’Brien. 2000. Tumor necrosis factor (TNF)-alpha and TNF receptors in viral pathogenesis. Proc. Soc. Exp. Biol. Med. 223: 241257.
76. Hickey, W. F. 1999. Leukocyte traffic in the central nervous system: the participants and their roles. Semin. Immunol. 11: 125137.
77. Hickey, W. F.,, B. L. Hsu, and, H. Kimura. 1991. T-lymphocyte entry into the central nervous system. J. Neurosci. Res. 28: 254260.
78. Hickey, W. F.,, K. Vass, and, H. Lassmann. 1992. Bone marrow-derived elements in the central nervous system: an immunohistochemical and ultrastructural survey of rat chimeras. J. Neuropathol. Exp. Neurol. 51: 246256.
79. Hijikata, M.,, N. Kato,, Y. Ootsuyama,, M. Nakagawa,, S. Ohkoshi, and, K. Shimotohno. 1991. Hypervariable regions in the putative glycoprotein of hepatitis C virus. Biochem. Biophys. Res. Commun. 175: 220228.
80. Hijikata, M.,, K. Mizuno,, T. Rikihisa,, Y. K. Shimizu,, A. Iwamoto,, N. Nakajima, and, H. Yoshikura. 1995. Selective transmission of hepatitis C virus in vivo and in vitro. Arch. Virol. 140: 16231628.
81. Hilsabeck, R. C.,, T. I. Hassanein,, M. D. Carlson,, E. A. Ziegler, and, W. Perry. 2003. Cognitive functioning and psychiatric symptomatology in patients with chronic hepatitis C. J. Int. Neuropsychol. Soc. 9: 847854.
82. Hilsabeck, R. C.,, W. Perry, and, T. I. Hassanein. 2002. Neuropsychological impairment in patients with chronic hepatitis C. Hepatology 35: 440446.
83. Hoffmann, R. M.,, H. M. Diepolder,, R. Zachoval,, F. M. Zwiebel,, M. C. Jung,, S. Scholz,, H. Nitschko,, G. Riethmuller, and, G. R. Pape. 1995. Mapping of immunodominant CD4+ T lymphocyte epitopes of hepatitis C virus antigens and their relevance during the course of chronic infection. Hepatology 21: 632638.
84. Kenny-Walsh, E., et al. 1999. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. N. Engl. J. Med. 340: 12281233.
85. Khabar, K. S.,, F. Al-Zoghaibi,, M. N. Al-Ahdal,, T. Murayama,, M. Dhalla,, N. Mukaida,, M. Taha,, S. T. Al-Sedairy,, Y. Siddiqui,, G. Kessie, and, K. Matsushima. 1997. The alpha chemokine, interleukin 8, inhibits the antiviral action of interferon alpha. J. Exp. Med. 186: 10771085.
86. Kibler, K.,, M. Radkowski,, D. Adair,, J. I. Arenas,, J. Wilkinson,, J. Rakela, and, T. Laskus. 2003. HCV inhibition of HIV-induced apoptosis. Hepatology 38: 352A.
87. Kiyosawa, K.,, T. Sodeyama,, E. Tanaka,, Y. Gibo,, K. Yoshizawa,, Y. Nakano,, S. Furuta,, Y. Akahane,, K. Nishioka,, R. H. Purcell, and, H. J. Alter. 1990. Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology 12: 671675.
88. Knopf, P. M.,, C. J. Harling-Berg,, H. F. Cserr,, D. Basu,, E. J. Sirulnick,, S. C. Nolan,, J. T. Park,, G. Keir,, E. J. Thompson, and, W. F. Hickey. 1998. Antigen-dependent intrathecal antibody synthesis in the normal rat brain: tissue entry and local retention of antigen-specific B cells. J. Immunol. 161: 692701.
89. Kojima, M.,, T. Osuga,, F. Tsuda,, T. Tanaka, and, H. Okamoto. 1994. Influence of antibodies to the hypervariable region of E2/NS1 glycoprotein on the selective replication of hepatitis C virus in chimpanzees. Virology 204: 665672.
90. Kolson, D. L.,, E. Lavi, and, F. Gonzalez-Scarano. 1998. The effects of human immunodeficiency virus in the central nervous system. Adv. Virus Res. 50: 147.
91. Kovacs, A.,, W. Du,, M. DeGiacomo,, T. Shahidyazdani,, D. Wright, and, J. Nowicki. 2004. Impact of HCV viremia on HIV disease progression in women, abstr. MoPeB3343. Abstr. 15th Int. AIDS Conf. July 11–16, 2004, Bangkok, Thailand.
92. Koziel, M. J.,, D. Dudley,, N. Afdhal,, Q. L. Choo,, M. Houghton,, R. Ralston, and, B. D. Walker. 1993. Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes recognize epitopes in the core and envelope proteins of HCV. J. Virol. 67: 75227532.
93. Koziel, M. J.,, D. Dudley,, N. Afdhal,, A. Grakoui,, C. M. Rice,, Q. L. Choo,, M. Houghton, and, B. D. Walker. 1995. HLA class I-restricted cytotoxic T lymphocytes specific for hepatitis C virus. Identification of multiple epitopes and characterization of patterns of cytokine release. J. Clin. Investig. 96: 23112321.
94. Koziel, M. J.,, D. Dudley,, J. T. Wong,, J. Dienstag,, M. Houghton,, R. Ralston, and, B. D. Walker. 1992. Intrahepatic cytotoxic T lymphocytes specific for hepatitis C virus in persons with chronic hepatitis. J. Immunol. 149: 33393344.
95. Kramer, L.,, E. Bauer,, G. Funk,, H. Hofer,, W. Jessner,, P. Steindl-Munda,, F. Wrba,, C. Madl,, A. Gangl, and, P. Ferenci. 2002. Subclinical impairment of brain function in chronic hepatitis C infection. J. Hepatol. 37: 349354.
96. Kudo, T.,, Y. Yanase,, M. Ohshiro,, M. Yamamoto,, M. Morita,, M. Shibata, and, T. Morishima. 1997. Analysis of mother-to-infant transmission of hepatitis C virus: quasispecies nature and buoyant densities of maternal virus populations. J. Med. Virol. 51: 225230.
97. Kumar, U.,, J. Monjardino, and, H. C. Thomas. 1994. Hypervariable region of hepatitis C virus envelope glycoprotein (E2/NS1) in an agammaglobulinemic patient. Gastroenterology 106: 10721075.
98. Kuo, G.,, Q. L. Choo,, H. J. Alter,, G. L. Gitnick,, A. G. Redeker,, R. H. Purcell,, T. Miyamura,, J. L. Dienstag,, M. J. Alter,, C. E. Stevens, et al. 1989. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 244: 362364.
99. Lane, B. R.,, K. Lore,, P. J. Bock,, J. Andersson,, M. J. Coffey,, R. M. Strieter, and, D. M. Markovitz. 2001. Interleukin-8 stimulates human immunodeficiency virus type 1 replication and is a potential new target for antiretroviral therapy. J. Virol. 75: 81958202.
100. Lanford, R. E.,, C. Sureau,, J. R. Jacob,, R. White, and, T. R. Fuerst. 1994. Demonstration of in vitro infection of chimpanzee hepatocytes with hepatitis C virus using strand-specific RT/PCR. Virology 202: 606614.
101. Laporte, J.,, C. Bain,, P. Maurel,, G. Inchauspe,, H. Agut, and, A. Cahour. 2003. Differential distribution and internal translation efficiency of hepatitis C virus quasispecies present in dendritic and liver cells. Blood 101: 5257.
102. Laporte, J.,, I. Malet,, T. Andrieu,, V. Thibault,, J. J. Toulme,, C. Wychowski,, J. M. Pawlotsky,, J. M. Huraux,, H. Agut, and, A. Cahour. 2000. Comparative analysis of translation efficiencies of hepatitis C virus 5′ untranslated regions among intraindividual quasispecies present in chronic infection: opposite behaviors depending on cell type. J. Virol. 74: 1082710833.
103. Laskus, T.,, M. Radkowski,, A. Bednarska,, J. Wilkinson,, D. Adair,, M. Nowicki,, G. B. Nikolopoulou,, H. Vargas, and, J. Rakela. 2002. Detection and analysis of hepatitis C virus sequences in cerebrospinal fluid. J. Virol. 76: 1006410068.
104. Laskus, T.,, M. Radkowski,, J. Jablonska,, K. Kibler,, J. Wilkinson,, D. Adair, and, J. Rakela. 2004a. Human immunodeficiency virus facilitates infection/replication of hepatitis C virus in native human macrophages. Blood 103: 38543859.
105. Laskus, T.,, M. Radkowski,, A. Piasek,, M. Nowicki,, A. Horban,, J. Cianciara, and, J. Rakela. 2000a. Hepatitis C virus in lymphoid cells of patients coinfected with human immunodeficiency virus type 1: evidence of active replication in monocytes/macrophages and lymphocytes. J. Infect. Dis. 181: 442448.
106. Laskus, T.,, M. Radkowski,, L. F. Wang,, S. J. Jang,, H. Vargas, and, J. Rakela. 1998a. Hepatitis C virus quasispecies in patients infected with HIV-1: correlation with extrahepatic viral replication. Virology 248: 164171.
107. Laskus, T.,, M. Radkowski,, L. F. Wang,, M. Nowicki, and, J. Rakela. 2000b. Uneven distribution of hepatitis C virus quasispecies in tissues from subjects with end-stage liver disease: confounding effect of viral adsorption and mounting evidence for the presence of low-level extrahepatic replication. J. Virol. 74: 10141017.
108. Laskus, T.,, M. Radkowski,, L. F. Wang,, H. Vargas, and, J. Rakela. 1997. Lack of evidence for hepatitis G virus replication in the livers of patients coinfected with hepatitis C and G viruses. J. Virol. 71: 78047806.
109. Laskus, T.,, M. Radkowski,, L. F. Wang,, H. Vargas, and, J. Rakela. 1998b. The presence of active hepatitis C virus replication in lymphoid tissue in patients coinfected with human immunodeficiency virus type 1. J. Infect. Dis. 178: 11891192.
110. Laskus, T.,, L. F. Wang,, M. Radkowski,, H. Vargas,, M. Nowicki,, J. Wilkinson, and, J. Rakela. 2001. Exposure of hepatitis C virus (HCV) RNA-positive recipients to HCV RNA-positive blood donors results in rapid predominance of a single donor strain and exclusion and/or suppression of the recipient strain. J. Virol. 75: 20592066.
111. Laskus, T.,, L. F. Wang,, J. Rakela,, H. Vargas,, A. D. Pinna,, A. C. Tsamandas,, A. J. Demetris, and, J. Fung. 1996. Dynamic behavior of hepatitis C virus in chronically infected patients receiving liver graft from infected donors. Virology 220: 171176.
112. Laskus, T.,, J. Wilkinson,, J. F. Gallegos-Orozco,, M. Radkowski,, D. M. Adair,, M. Nowicki,, E. Operskalski,, Z. Buskell,, L. B. Seeff,, H. Vargas, and, J. Rakela. 2004b. Analysis of hepatitis C virus quasispecies transmission and evolution in patients infected through blood transfusion. Gastroenterology 127: 764776.
113. Lau, D. T.,, D. E. Kleiner,, M. G. Ghany,, Y. Park,, P. Schmid, and, J. H. Hoofnagle. 1998. 10-Year follow-up after interferon-alpha therapy for chronic hepatitis C. Hepatology 28: 11211127.
114. Lee, W. M.,, J. E. Polson,, D. S. Carney,, B. Sahin, and, M. Gale, Jr. 2005. Reemergence of hepatitis C virus after 8.5 years in a patient with hypogammaglobulinemia: evidence for an occult viral reservoir. J. Infect. Dis. 192: 10881092.
115. Lehmann, C.,, H. Sprenger,, M. Nain,, M. Bacher, and, D. Gemsa. 1996. Infection of macrophages by influenza A virus: characteristics of tumour necrosis factor-alpha (TNF alpha) gene expression. Res. Virol. 147: 123130.
116. Lerat, H.,, S. Rumin,, F. Habersetzer,, F. Berby,, M. A. Trabaud,, C. Trepo, and, G. Inchauspe. 1998. In vivo tropism of hepatitis C virus genomic sequences in hematopoietic cells: influence of viral load, viral genotype, and cell phenotype. Blood 91: 38413849.
117. Lerat, H.,, Y. K. Shimizu, and, S. M. Lemon. 2000. Cell type-specific enhancement of hepatitis C virus internal ribosome entry site-directed translation due to 5′ nontranslated region substitutions selected during passage of virus in lymphoblastoid cells. J. Virol. 74: 70247031.
118. Lesens, O.,, M. Deschenes,, M. Steben,, G. Belanger, and, C. M. Tsoukas. 1999. Hepatitis C virus is related to progressive liver disease in human immunodeficiency virus-positive hemophiliacs and should be treated as an opportunistic infection. J. Infect. Dis. 179: 12541258.
119. Letendre, S. L.,, M. Cherner,, R. Ellis, and, I. Grant. 2002. Individuals coinfected with hepatitis C (HCV) and HIV are more cognitively impaired than those infected with either virus alone. J. Neurovirol. 8: 2728 (Abstract.)
120. Li, Y.,, X. Wang,, S. D. Douglas,, D. S. Metzger,, G. Woody,, T. Zhang,, L. Song, and, W. Z. Ho. 2005. CD8+ T cell depletion amplifies hepatitis C virus replication in peripheral blood mononuclear cells. J. Infect. Dis. 192: 10931101.
121. Lindsay, K. L. 2002. Introduction to therapy of hepatitis C. Hepatology 36: S114S120.
122. Lyles, D. S. 2000. Cytopathogenesis and inhibition of host gene expression by RNA viruses. Microbiol. Mol. Biol. Rev. 64: 709724.
123. Maggi, F.,, M. Giorgi,, C. Fornai,, A. Morrica,, M. L. Vatteroni,, M. Pistello,, G. Siciliano,, A. Nuccorini, and, M. Bendinelli. 1999. Detection and quasispecies analysis of hepatitis C virus in the cerebrospinal fluid of infected patients. J. Neurovirol. 5: 319323.
124. Mahe, Y.,, N. Mukaida,, K. Kuno,, M. Akiyama,, N. Ikeda,, K. Matsushima, and, S. Murakami. 1991. Hepatitis B virus X protein transactivates human interleukin-8 gene through acting on nuclear factor kB and CCAAT/enhancer-binding protein-like cis-elements. J. Biol. Chem. 266: 1375913763.
125. Major, M. E.,, K. Mihalik,, J. Fernandez,, J. Seidman,, D. Kleiner,, A. A. Kolykhalov,, C. M. Rice, and, S. M. Feinstone. 1999. Long-term follow-up of chimpanzees inoculated with the first infectious clone for hepatitis C virus. J. Virol. 73: 33173325.
126. Manzin, A.,, L. Solforosi,, E. Petrelli,, G. Macarri,, G. Tosone,, M. Piazza, and, M. Clementi. 1998. Evolution of hypervariable region 1 of hepatitis C virus in primary infection. J. Virol. 72: 62716276.
127. Mao, Q.,, S. C. Ray,, O. Laeyendecker,, J. R. Ticehurst,, S. A. Strathdee,, D. Vlahov, and, D. L. Thomas. 2001. Human immunodeficiency virus seroconversion and evolution of the hepatitis C virus quasispecies. J. Virol. 75: 32593267.
128. Marcus, C. D.,, S. D. Taylor-Robinson,, J. Sargentoni,, J. G. Ainsworth,, G. Frize,, P. J. Easterbrook,, S. Shaunak, and, D. J. Bryant. 1998. 1H MR spectroscopy of the brain in HIV-1-seropositive subjects: evidence for diffuse metabolic abnormalities. Metab. Brain Dis. 13: 123136.
129. Martell, M.,, J. I. Esteban,, J. Quer,, J. Genesca,, A. Weiner,, R. Esteban,, J. Guardia, and, J. Gomez. 1992. Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution. J. Virol. 66: 32253229.
130. Martell, M.,, J. I. Esteban,, J. Quer,, V. Vargas,, R. Esteban,, J. Guardia, and, J. Gomez. 1994. Dynamic behavior of hepatitis C virus quasispecies in patients undergoing orthotopic liver transplantation. J. Virol. 68: 34253436.
131. McAndrews, M. P.,, K. Farcnik,, P. Carlen,, A. Damyanovich,, M. Mrkonjic,, S. Jones, and, E. J. Heathcote. 2005. Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors. Hepatology 41: 801808.
132. McHutchison, J. G.,, G. Davis,, L., R. Esteban-Mur,, T. Poynard,, M. H. Ling,, J. J. Garaud,, J. K. Albrecht, et al. 2001. Durability of sustained virologic response in patients with chronic hepatitis C after treatment with interferon alpha-2B alone or in combination with ribavirin. Hepatology 34: 244A. (Abstract.)
133. Meyerhoff, D. J.,, C. Bloomer,, V. Cardenas,, D. Norman,, M. W. Weiner, and, G. Fein. 1999. Elevated subcortical choline metabolites in cognitively and clinically asymptomatic HIV+ patients. Neurology 52: 9951003.
134. Michalak, T. I.,, P. M. Mulrooney, and, C. S. Coffin. 2004. Low doses of hepadnavirus induce infection of the lymphatic system that does not engage the liver. J. Virol. 78: 17301738.
135. Minagar, A.,, P. Shapshak,, R. Fujimura,, R. Ownby,, M. Heyes, and, C. Eisdorfer. 2002. The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. J. Neurol. Sci. 202: 1323.
136. Miro, O.,, S. Lopez,, E. Martinez,, E. Pedrol,, A. Milinkovic,, E. Deig,, G. Garrabou,, J. Casademont,, J. M. Gatell, and, F. Cardellach. 2004. Mitochondrial effects of HIV infection on the peripheral blood mononuclear cells of HIV-infected patients who were never treated with antiretrovirals. Clin. Infect. Dis. 39: 710716.
137. Mogensen, S. C. 1979. Role of macrophages in natural resistance to virus infections. Microbiol. Rev. 43: 126.
138. Mollace, V.,, H. S. Nottet,, P. Clayette,, M. C. Turco,, C. Muscoli,, D. Salvemini, and, C. F. Perno. 2001. Oxidative stress and neuroAIDS: triggers, modulators and novel antioxidants. Trends Neurosci. 24: 411416.
139. Monga, H. K.,, K. Breauz,, M. C. Rodrigues-Barradas, and, B. Yoffe. 1998. Increased HCV-related morbidity and mortality in HIV patients. Hepatology 28: 565A.
140. Mori, N.,, N. Mukaida,, D. W. Ballard,, K. Matsushima, and, N. Yamamoto. 1998. Human T-cell leukemia virus type I Tax transactivates human interleukin 8 gene through acting concurrently on AP-1 and nuclear factor-kappaB-like sites. Cancer Res. 58: 39934000.
141. Morsica, G.,, M. T. Bernardi,, R. Novati,, C. Uberti Foppa,, A. Castagna, and, A. Lazzarin. 1997. Detection of hepatitis C virus genomic sequences in the cerebrospinal fluid of HIV-infected patients. J. Med. Virol. 53: 252254.
142. Mukaida, N. 2000. Interleukin-8: an expanding universe beyond neutrophil chemotaxis and activation. Int. J. Hematol. 72: 391398.
143. Murayama, T.,, K. Kuno,, F. Jisaki,, M. Obuchi,, D. Sakamuro,, T. Furukawa,, N. Mukaida, and, K. Matsushima. 1994. Enhancement human cytomegalovirus replication in a human lung fibroblast cell line by interleukin-8. J. Virol. 68: 75827585.
144. Murayama, T.,, Y. Ohara,, M. Obuchi,, K. S. Khabar,, H. Higashi,, N. Mukaida, and, K. Matsushima. 1997. Human cytomegalovirus induces interleukin-8 production by a human monocytic cell line, THP-1, through acting concurrently on AP-1- and NF-kappaB-binding sites of the interleukin-8 gene. J. Virol. 71: 56925695.
145. Nakajima, N.,, M. Hijikata,, H. Yoshikura, and, Y. K. Shimizu. 1996. Characterization of long-term cultures of hepatitis C virus. J. Virol. 70: 33253329.
146. Nasoff, M. S.,, S. L. Zebedee,, G. Inchauspe, and, A. M. Prince. 1991. Identification of an immunodominant epitope within the capsid protein of hepatitis C virus. Proc. Natl. Acad. Sci. USA 88: 54625466.
147. Navas, S.,, J. Martin,, J. A. Quiroga,, I. Castillo, and, V. Carreno. 1998. Genetic diversity and tissue compartmentalization of the hepatitis C virus genome in blood mononuclear cells, liver, and serum from chronic hepatitis C patients. J. Virol. 72: 16401646.
148. Neumann, A. U.,, N. P. Lam,, H. Dahari,, D. R. Gretch,, T. E. Wiley,, T. J. Layden, and, A. S. Perelson. 1998. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 282: 103107.
149. Ni, J.,, E. Hembrador,, A. M. Di Bisceglie,, I. M. Jacobson,, A. H. Talal,, D. Butera,, C. M. Rice,, T. J. Chambers, and, L. B. Dustin. 2003. Accumulation of B lymphocytes with a naive, resting phenotype in a subset of hepatitis C patients. J. Immunol. 170: 34293439.
150. Nicholls, D. G.,, and S. L. Budd. 2000. Mitochondria and neuronal survival. Physiol. Rev. 80: 315360.
151. Nishioka, K. 1994. Epidemiological studies on hepatitis C virus infection: detection, prevalence, exposure and prevention. Intervirology 37: 5867.
152. Nousbaum, J. B.,, S. Pol,, B. Nalpas,, P. Landais,, P. Berthelot,, C. Brechot, et al. 1995. Hepatitis C virus type 1b (II) infection in France and Italy. Ann. Intern. Med. 122: 161168.
153. Nowicki, M. J.,, T. Laskus,, G. Nikolopoulou,, M. Radkowski,, J. Wilkinson,, W. B. Du,, J. Rakela, and, A. Kovacs. 2005. Presence of hepatitis C virus (HCV) RNA in the genital tracts of HCV/HIV-1-coinfected women. J. Infect. Dis. 192: 15571565.
154. Ogata, N.,, H. J. Alter,, R. H. Miller, and, R. H. Purcell. 1991. Nucleotide sequence and mutation rate of the H strain of hepatitis C virus. Proc. Natl. Acad. Sci. USA 88: 33923396.
155. Okamoto, H.,, M. Kojima,, S. Okada,, H. Yoshizawa,, H. Iizuka,, T. Tanaka,, E. E. Muchmore,, D. A. Peterson,, Y. Ito, and, S. Mishiro. 1992. Genetic drift of hepatitis C virus during an 8.2-year infection in a chimpanzee: variability and stability. Virology 190: 894899.
156. Okamoto, H.,, S. Mishiro,, H. Tokita,, F. Tsuda,, Y. Miyakawa, and, M. Mayumi. 1994. Superinfection of chimpanzees carrying hepatitis C virus of genotype II/1b with that of genotype III/2a or I/1a. Hepatology 20: 11311136.
157. Okuda, M.,, K. Li,, M. R. Beard,, L. A. Showalter,, F. Scholle,, S. M. Lemon, and, S. A. Weinman. 2002. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 122: 366375.
158. Oldstone, M. B. 1996. Virus-lymphoid cell interactions. Proc. Natl. Acad. Sci. USA 93: 1275612758.
159. Origgi, L.,, M. Vanoli,, A. Carbone,, M. Grasso, and, R. Scorza. 1998. Central nervous system involvement in patients with HCV-related cryoglobulinemia. Am. J. Med. Sci. 315: 208210.
160. Orth, M.,, and A. H. Schapira. 2001. Mitochondria and degenerative disorders. Am. J. Med. Genet. 106: 2736.
161. Papaevangelou, V.,, H. Pollack,, G. Rochford,, R. Kokka,, Z. Hou,, D. Chernoff,, B. Hanna,, K. Krasinski, and, W. Borkowsky. 1998. Increased transmission of vertical hepatitis C virus (HCV) infection to human immunodeficiency virus (HIV)-infected infants of HIV- and HCV-coinfected women. J. Infect. Dis. 178: 10471052.
162. Petrov, T.,, B. D. Underwood,, B. Braun,, S. S. Alousi, and, J. A. Rafols. 2001. Upregulation of iNOS expression and phosphorylation of eIF-2alpha are paralleled by suppression of protein synthesis in rat hypothalamus in a closed head trauma model. J. Neurotrauma 18: 799812.
163. Pham, T. N.,, S. A. MacParland,, P. M. Mulrooney,, H. Cooksley,, N. V. Naoumov, and, T. I. Michalak. 2004. Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C. J. Virol. 78: 58675874.
164. Piroth, L.,, M. Duong,, C. Quantin,, M. Abrahamowicz,, R. Michardiere,, L. S. Aho,, M. Grappin,, M. Buisson,, A. Waldner,, H. Portier, and, P. Chavanet. 1998. Does hepatitis C virus co-infection accelerate clinical and immunological evolution of HIV-infected patients? AIDS 12: 381388.
165. Polyak, S. J.,, K. S. Khabar,, D. M. Paschal,, H. J. Ezelle,, G. Duverlie,, G. N. Barber,, D. E. Levy,, N. Mukaida, and, D. R. Gretch. 2001a. Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. J. Virol. 75: 60956106.
166. Polyak, S. J.,, K. S. Khabar,, M. Rezeiq, and, D. R. Gretch. 2001b. Elevated levels of interleukin-8 in serum are associated with hepatitis C virus infection and resistance to interferon therapy. J. Virol. 75: 62096211.
167. Post, J. J.,, Y. Pan,, A. J. Freeman,, C. E. Harvey,, P. A. White,, P. Palladinetti,, P. S. Haber,, G. Marinos,, M. H. Levy,, J. M. Kaldor,, K. A. Dolan,, R. A. Ffrench,, A. R. Lloyd, and, W. D. Rawlinson. 2004. Clearance of hepatitis C viremia associated with cellular immunity in the absence of seroconversion in the hepatitis C incidence and transmission in prisons study cohort. J. Infect. Dis. 189: 18461855.
168. Price, R. W.,, J. Sidtis, and, M. Rosenblum. 1988. The AIDS dementia complex: some current questions. Ann. Neurol. 23: S27S33.
169. Prince, A. M.,, B. Brotman,, T. Huima,, D. Pascual,, M. Jaffery, and, G. Inchauspe. 1992. Immunity in hepatitis C infection. J. Infect. Dis. 165: 438443.
170. Pulliam, L.,, B. G. Herndier,, N. M. Tang, and, M. S. McGrath. 1991. Human immunodeficiency virus-infected macrophages produce soluble factors that cause histological and neurochemical alterations in cultured human brains. J. Clin. Investig. 87: 503512.
171. Purcell, R. 1997. The hepatitis C virus: overview. Hepatology 26: 11S14S.
172. Qadri, I.,, M. Iwahashi,, J. M. Capasso,, M. W. Hopken,, S. Flores,, J. Schaack, and, F. R. Simon. 2004. Induced oxidative stress and activated expression of manganese superoxide dismutase during hepatitis C virus replication: role of JNK, p38 MAPK and AP-1. Biochem. J. 378: 919928.
173. Radkowski, M.,, A. Bednarska,, A. Horban,, J. Stanczak,, J. Wilkinson,, D. M. Adair,, M. Nowicki,, J. Rakela, and, T. Laskus. 2004a. Infection of primary human macrophages with hepatitis C virus in vitro: induction of tumour necrosis factor-alpha and interleukin 8. J. Gen. Virol. 85: 4759.
174. Radkowski, M.,, J. F. Gallegos-Orozco,, J. Jablonska,, T. V. Colby,, B. Walewska-Zielecka,, J. Kubicka,, J. Wilkinson,, D. Adair,, J. Rakela, and, T. Laskus. 2004b. Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C. Hepatology 41: 106114.
175. Radkowski, M.,, L. F. Wang,, H. E. Vargas,, J. Rakela, and, T. Laskus. 1998. Detection of hepatitis C virus replication in peripheral blood mononuclear cells after orthotopic liver transplantation. Transplantation 66: 664666.
176. Radkowski, M.,, J. Wilkinson,, M. Nowicki,, D. Adair,, H. Vargas,, C. Ingui,, J. Rakela, and, T. Laskus. 2002. Search for hepatitis C virus negative-strand RNA sequences and analysis of viral sequences in the central nervous system: evidence of replication. J. Virol. 76: 600608.
177. Ray, S. C.,, Y. M. Wang,, O. Laeyendecker,, J. R. Ticehurst,, S. A. Villano, and, D. L. Thomas. 1999. Acute hepatitis C virus structural gene sequences as predictors of persistent viremia: hypervariable region 1 as a decoy. J. Virol. 73: 29382946.
178. Reichard, O.,, H. Glaumann,, A. Fryden,, G. Norkrans,, R. Wejstal, and, O. Weiland. 1999. Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon. J. Hepatol. 30: 783787.
179. Richardson, J. L.,, M. Nowicki,, K. Danley,, E. M. Martin,, M. H. Cohen,, R. Gonzalez,, J. Vassileva, and, A. M. Levine. 2005. Neuropsychological functioning in a cohort of HIV- and hepatitis C virus-infected women. AIDS 19: 16591667.
180. Ridzon, R.,, K. Gallagher,, C. Ciesielski,, M. B. Ginsberg,, B. J. Robertson,, C. C. Luo, and, A. DeMaria, Jr. 1997. Simultaneous transmission of human immunodeficiency virus and hepatitis C virus from a needle-stick injury. N. Engl. J. Med. 336: 919922.
181. Roque-Afonso, A. M.,, D. Ducoulombier,, G. Di Liberto,, R. Kara,, M. Gigou,, E. Dussaix,, D. Samuel, and, C. Feray. 2005. Compartmentalization of hepatitis C virus genotypes between plasma and peripheral blood mononuclear cells. J. Virol. 79: 63496357.
182. Ryan, E. L.,, S. Morgello,, K. Isaacs,, M. Naseer, and, P. Gerits. 2004. Neuropsychiatric impact of hepatitis C on advanced HIV. Neurology 62: 957962.
183. Sabin, C. A.,, P. Telfer,, A. N. Phillips,, S. Bhagani, and, C. A. Lee. 1997. The association between hepatitis C virus genotype and human immunodeficiency virus disease progression in a cohort of hemophilic men. J. Infect. Dis. 175: 164168.
184. Sacktor, N. C.,, H. Bacellar,, D. R. Hoover,, T. E. Nance-Sproson,, O. A. Selnes,, E. N. Miller,, G. J. Dal Pan,, C. Kleeberger,, A. Brown,, A. Saah, and, J. C. McArthur. 1996. Psychomotor slowing in HIV infection: a predictor of dementia, AIDS and death. J. Neurovirol. 2: 404410.
185. Saiz, J. C.,, S. Lopez de Quinto,, N. Ibarrola,, F. X. Lopez-Labrador,, J. M. Sanchez-Tapias,, J. Rodes, and, E. Martinez-Salas. 1999. Internal initiation of translation efficiency in different hepatitis C genotypes isolated from interferon treated patients. Arch. Virol. 144: 215229.
186. Sansonno, D.,, A. R. Iacobelli,, V. Cornacchiulo,, G. Iodice, and, F. Dammacco. 1996. Detection of hepatitis C virus (HCV) proteins by immunofluorescence and HCV RNA genomic sequences by non-isotopic in situ hybridization in bone marrow and peripheral blood mononuclear cells of chronically HCV- infected patients. Clin. Exp. Immunol. 103: 414421.
187. Saraste, M. 1999. Oxidative phosphorylation at the fin de siecle. Science 283: 14881493.
188. Scarselli, E.,, A. Cerino,, G. Esposito,, E. Silini,, M. U. Mondelli, and, C. Traboni. 1995. Occurrence of antibodies reactive with more than one variant of the putative envelope glycoprotein (gp70) hypervariable region 1 in viremic hepatitis C virus-infected patients. J. Virol. 69: 44074412.
189. Schupper, H.,, P. Hayashi,, J. Scheffel,, S. Aceituno,, T. Paglieroni,, P. V. Holland, and, J. B. Zeldis. 1993. Peripheral-blood mononuclear cell responses to recombinant hepatitis C virus antigens in patients with chronic hepatitis C. Hepatology 18: 10551060.
190. Schwer, B.,, S. Ren,, T. Pietschmann,, J. Kartenbeck,, K. Kaehlcke,, R. Bartenschlager,, T. S. Yen, and, M. Ott. 2004. Targeting of hepatitis C virus core protein to mitochondria through a novel C-terminal localization motif. J. Virol. 78: 79587968.
191. Seeff, L. B.,, F. B. Hollinger,, H. J. Alter,, E. C. Wright,, C. M. Cain,, Z. J. Buskell,, K. G. Ishak,, F. L. Iber,, D. Toro,, A. Samanta,, R. L. Koretz,, R. P. Perrillo,, Z. D. Goodman,, R. G. Knodell,, G. Gitnick,, T. R. Morgan,, E. R. Schiff,, S. Lasky,, C. Stevens,, R. Z. Vlahcevic,, E. Weinshel,, T. Tanwandee,, H. J. Lin, and, L. Barbosa. 2001. Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: a National Heart, Lung, and Blood Institute collaborative study. Hepatology 33: 455463.
192. Shata, M. T.,, N. Tricoche,, M. Perkus,, D. Tom,, B. Brotman,, P. McCormack,, W. Pfahler,, D. H. Lee,, L. H. Tobler,, M. Busch, and, A. M. Prince. 2003. Exposure to low infective doses of HCV induces cellular immune responses without consistently detectable viremia or seroconversion in chimpanzees. Virology 314: 601616.
193. Sherman, K. E.,, J. O’Brien,, A. G. Gutierrez,, S. Harrison,, M. Urdea,, P. Neuwald, and, J. Wilber. 1993. Quantitative evaluation of hepatitis C virus RNA in patients with concurrent human immunodeficiency virus infections. J. Clin. Microbiol. 31: 26792682.
194. Shimizu, Y. K.,, H. Igarashi,, T. Kanematu,, K. Fujiwara,, D. C. Wong,, R. H. Purcell, and, H. Yoshikura. 1997. Sequence analysis of the hepatitis C virus genome recovered from serum, liver, and peripheral blood mononuclear cells of infected chimpanzees. J. Virol. 71: 57695773.
195. Shimizu, Y. K.,, R. H. Purcell, and, H. Yoshikura. 1993. Correlation between the infectivity of hepatitis C virus in vivo and its infectivity in vitro. Proc. Natl. Acad. Sci. USA 90: 60376041.
196. Shindo, M.,, A. M. Di Bisceglie,, R. Biswas,, K. Mihalik, and, S. M. Feinstone. 1992. Hepatitis C virus replication during acute infection in the chimpanzee. J. Infect. Dis. 166: 424427.
197. Shirai, M.,, T. Arichi,, M. Chen,, T. Masaki,, M. Nishioka,, K. Ikeda,, H. Takahashi,, N. Enomoto,, T. Saito,, M. E. Major,, T. Nakazawa,, T. Akatsuka,, S. M. Feinstone, and, J. A. Berzofsky. 1999. T cell recognition of hypervariable region-1 from hepatitis C virus envelope protein with multiple class II MHC molecules in mice and humans: preferential help for induction of antibodies to the hypervariable region. J. Immunol. 162: 568576.
198. Shirai, M.,, H. Okada,, M. Nishioka,, T. Akatsuka,, C. Wychowski,, R. Houghten,, C. D. Pendleton,, S. M. Feinstone, and, J. A. Berzofsky. 1994. An epitope in hepatitis C virus core region recognized by cytotoxic T cells in mice and humans. J. Virol. 68: 33343342.
199. Simonetti, R. G.,, C. Camma,, F. Fiorello,, M. Cottone,, M. Rapicetta,, L. Marino,, G. Fiorentino,, A. Craxi,, A. Ciccaglione,, R. Giuseppetti,, T. Stroffolini, and, L. Pagliaro. 1992. Hepatitis C virus infection as a risk factor for hepatocellular carcinoma in patients with cirrhosis. A case-control study. Ann. Intern. Med. 116: 97102.
200. Singh, N.,, T. Gayowski,, M. M. Wagener, and, I. R. Marino. 1999. Quality of life, functional status, and depression in male liver transplant recipients with recurrent viral hepatitis C. Transplantation 67: 6972.
201. Smith, D. B.,, J. McAllister,, C. Casino, and, P. Simmonds. 1997. Virus ‘quasispecies’: making a mountain out of a molehill? J. Gen. Virol. 78: 15111519.
202. Smith, D. B.,, J. Mellor,, L. M. Jarvis,, F. Davidson,, J. Kolberg,, M. Urdea,, P. L. Yap,, P. Simmonds, et al. 1995. Variation of the hepatitis C virus 5′ non-coding region: implications for secondary structure, virus detection and typing. J. Gen. Virol. 76: 17491761.
203. Song, G.,, V. K. Dhodda,, A. T. Blei,, R. J. Dempsey, and, V. L. Rao. 2002. GeneChip analysis shows altered mRNA expression of transcripts of neurotransmitter and signal transduction pathways in the cerebral cortex of portacaval shunted rats. J. Neurosci. Res. 68: 730737.
204. Steinhauer, D. A.,, and J. J. Holland. 1987. Rapid evolution of RNA viruses. Annu. Rev. Microbiol. 41: 409433.
205. Sugitani, M.,, and T. Shikata. 1998. Comparison of amino acid sequences in hypervariable region-1 of hepatitis C virus clones between human inocula and the infected chimpanzee sera. Virus Res. 56: 177182.
206. Sulkowski, M. S.,, R. D. Moore,, S. H. Mehta,, R. E. Chaisson, and, D. L. Thomas. 2002. Hepatitis C and progression of HIV disease. JAMA 288: 199206.
207. Swain, M.,, E. J. Heathcote,, L. M.Y.,, V. Bain,, V. Feinman,, M. Sherman,, K. D. Kaita,, E. Gane,, K. Peltekian, and, K. L. Lindsay. 2001. Long-lasting sustained virological response in chronic hepatitis C patients previously treated with 40 kD peginterferon alpha-2A (Pegasys). Hepatology 34: 330A. (Abstract.)
208. Takaki, A.,, M. Wiese,, G. Maertens,, E. Depla,, U. Seifert,, A. Liebetrau,, J. L. Miller,, M. P. Manns, and, B. Rehermann. 2000. Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C. Nat. Med. 6: 578582.
209. Taylor, M. J.,, S. L. Letendre,, B. C. Schweinsburg,, O. M. Alhassoon,, G. G. Brown,, A. Gongvatana, and, I. Grant. 2004. Hepatitis C virus infection is associated with reduced white matter N-acetylaspartate in abstinent methamphetamine users. J. Int. Neuropsychol. Soc. 10: 110113.
210. Taylor-Robinson, S. D. 2001. Applications of magnetic resonance spectroscopy to chronic liver disease. Clin. Med. 1: 5460.
211. Thelu, M. A.,, E. Drouet,, M. N. Hilleret, and, J. P. Zarski. 2004. Lack of clinical significance of variability in the internal ribosome entry site of hepatitis C virus. J. Med. Virol. 72: 396405.
212. Thimme, R.,, J. Bukh,, H. C. Spangenberg,, S. Wieland,, J. Pemberton,, C. Steiger,, S. Govindarajan,, R. H. Purcell, and, F. V. Chisari. 2002. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc. Natl. Acad. Sci. USA 99: 1566115668.
213. Thimme, R.,, D. Oldach,, K. M. Chang,, C. Steiger,, S. C. Ray, and, F. V. Chisari. 2001. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J. Exp. Med. 194: 13951406.
214. Thomas, D. L.,, J. D. Rich,, P. Schuman,, D. K. Smith,, J. A. Astemborski,, K. R. Nolt, and, R. S. Klein. 2001. Multicenter evaluation of hepatitis C RNA levels among female injection drug users. J. Infect. Dis. 183: 973976.
215. Thomas, S. L.,, M. L. Newell,, C. S. Peckham,, A. E. Ades, and, A. J. Hall. 1998. A review of hepatitis C virus (HCV) vertical transmission: risks of transmission to infants born to mothers with and without HCV viraemia or human immunodeficiency virus infection. Int. J. Epidemiol. 27: 108117.
216. Tovo, P. A.,, E. Palomba,, G. Ferraris,, N. Principi,, E. Ruga,, P. Dallacasa,, A. Maccabruni, et al. 1997. Increased risk of maternal-infant hepatitis C virus transmission for women coinfected with human immunodeficiency virus type 1. Clin. Infect. Dis. 25: 11211124.
217. Toyoda, H.,, Y. Fukuda,, Y. Koyama,, J. Takamatsu,, H. Saito, and, T. Hayakawa. 1997. Effect of immunosuppression on composition of quasispecies population of hepatitis C virus in patients with chronic hepatitis C coinfected with human immunodeficiency virus. J. Hepatol. 26: 975982.
218. Tsukiyama-Kohara, K.,, N. Iizuka,, M. Kohara, and, A. Nomoto. 1992. Internal ribosome entry site within hepatitis C virus RNA. J. Virol. 66: 14761483.
219. Unger, E. R.,, J. H. Sung,, J. C. Manivel,, M. L. Chenggis,, B. R. Blazar, and, W. Krivit. 1993. Male donor-derived cells in the brains of female sex-mismatched bone marrow transplant recipients: a Y-chromosome specific in situ hybridization study. J. Neuropathol. Exp. Neurol. 52: 460470.
220. van’t Wout, A. B.,, N. A. Kootstra,, G. A. Mulder-Kampinga,, N. Albrecht-van Lent,, H. J. Scherpbier,, J. Veenstra,, K. Boer,, R. A. Coutinho,, F. Miedema, and, H. Schuitemaker. 1994. Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission. J. Clin. Investig. 94: 20602067.
221. von Giesen, H. J.,, T. Heintges,, N. Abbasi-Boroudjeni,, S. Kucukkoylu,, H. Koller,, B. A. Haslinger,, M. Oette, and, G. Arendt. 2004. Psychomotor slowing in hepatitis C and HIV infection. J. Acquir. Immune Defic. Syndr. 35: 131137.
222. Wang, C.,, P. Sarnow, and, A. Siddiqui. 1994. A conserved helical element is essential for internal initiation of translation of hepatitis C virus RNA. J. Virol. 68: 73017307.
223. Warskulat, U.,