Antiapoptotic and oncogenic potentials of hepatitis C virus are linked to interferon resistance by viral repression of the PKR protein kinase

Journal of Virology

Volumn 73, Issue 8, 1999, Pages 6506-6516

  Gale Jr , Michael ^a,c   Kwieciszewski, Bart ^b   Dossett, Michelle ^a   Nakao, Haruhisa ^b   Katze, Michael G ^a,b  

^a UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF WASHINGTON   (United States)

^c UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

INTERFERON; PROTEIN KINASE;

ANIMAL CELL; APOPTOSIS; ARTICLE; CARCINOGENICITY; HOST CELL; IMMUNE RESPONSE; MEDIATOR RELEASE; MOUSE; NONHUMAN; PERSISTENT VIRUS INFECTION; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN PHOSPHORYLATION; RNA TRANSLATION; TUMOR SUPPRESSOR GENE; VIRUS EXPRESSION; VIRUS INFECTION; VIRUS INHIBITION;

EID: 0345004984     PISSN: 0022538X     EISSN: None     Source Type: Journal    
DOI: 10.1128/jvi.73.8.6506-6516.1999     Document Type: Article

References (91)

1. Aktas, H., R. Fluckiger, J. Acosta, J. Savage, S. Palakurthi, and J. Halperin. 1998. Depletion of intracellular calcium stores, phosphorylation of eIF-2α, and sustained inhibition of translation mediate the anticancer effects of clotrimazole. Proc. Natl. Acad. Sci. USA 95:8280-8285.
2. Alter, M. J. H. 1997. Epidemiology of hepatitis C. Hepatology 24:62-65.
3. Amoroso, P., M. Rapicetta, M. E. M. A. Tosti, E. Spada, S. Bounocore, G. Lettieri, P. Peirri, P. Chionne, A. R. Ciccaglione, and L. Sagliocca. 1998. Correlation between virus genotype and chronicity rate in acute hepatitis C. J. Hepatol. 28:939-944.
4. Balachandran, S., C. N. Kim, W.-C. Yeh, T. W. Mak, and G. N. Barber. 1998. Activation of the dsRNA-dependent protein kinase, PKR, induces apoptosis through FADD-mediated death signaling. EMBO J. 17:6888-6902.
5. Barber, G. N., R. Jagus, E. F. Meurs, A. G. Hovanessian, and M. G. Katze. 1995. Molecular mechanisms responsible for malignant transformation by regulatory and catalytic domain variants of the interferon-induced enzyme RNA-dependent protein kinase. J. Biol. Chem. 270:17423-17428.
6. Barber, G. N., S. Thompson, T. G. Lee, T. Strom, R. Jagus, A. Darveau, and M. G. Katze. 1994. The 58-kilodalton inhibitor of the interferon-induced double-stranded RNA-activated protein kinase is a tetratricopeptide repeat protein with oncogenic properties. Proc. Natl. Acad. Sci. USA 91:4278-4282.
7. Barber, G. N., M. Wambach, S. Thompson, R. Jagus, and M. G. Katze. 1995. Mutants of the RNA-dependent protein kinase (PKR) lacking double-stranded RNA binding domain I can act as transdominant inhibitors and induce malignant transformation. Mol. Cell. Biol. 15:3138-3146.
8. Benkirane, M., C. Neuveut, R. F. Chun, S. M. Smith, C. E. Samuel, A. Gatignol, and K.-T. Jeang. 1997. Oncogenic potential of TAR RNA binding protein TRBP and its regulatory interaction with RNA-dependent protein kinase PKR. EMBO J. 16:611-624.
9. Beyaert, R., and W. Fiers. 1994. Molecular mechanisms of tumor necrosis factor-induced cytotoxicity. What we do understand and what we do not. FEBS Lett. 340:9-16.
10. Blight, K. J., and C. M. Rice. 1997. Secondary structure determination of the conserved 98-base sequence at the 3′ terminus of hepatitis C virus genome RNA. J. Virol. 71:7345-7352.
11. Bruno, S., E. Silini, A. Crosignani, F. Borzio, G. Leandro, F. Bono, M. Asti, S. Rossi, A. Larghi, A. Cerino, M. Podda, and M. U. Mondelli. 1997. Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: a prospective study. Hepatology 25:754-758.
12. Bukh, J., R. Miller, and R. Purcell. 1995. Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes. Semin. Liver Dis. 15:41-63.
13. Chang, J., S.-H. Yang, Y.-G. Cho, S. B. Hwang, Y. S. Hahn, and Y. C. Sung. 1998. Hepatitis C virus core from two different genotypes has an oncogenic potential but is not sufficient for transforming primary rat embryo fibroblasts in cooperation with the H-ras oncogene. J. Virol. 72:3060-3065.
14. Chayama, K., A. Tsubota, M. Kobayashi, K. Okamoto, M. Hashimoto, Y. Miyano, H. Koike, I. Koida, Y. Arase, S. Saitoh, Y. Suzuki, N. Murashima, K. Ikeda, and H. Kumada. 1997. Pretreatment virus load and multiple amino acid substitutions in the interferon sensitivity-determining region predict the outcome of interferon treatment in patients with chronic genotype 1b hepatitis C virus infection. Hepatology 25:745-749.
15. Chen, J.-J., and I. M. London. 1995. Regulation of protein synthesis by heme-regulated eIF-2α kinase. Trends Biochem. Sci. 20:105-108.
16. 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 244:359-362.
17. Clemens, M. J., and A. Elia. 1997. The double-stranded RNA-dependent protein kinase PKR: structure and function. J. Interferon Cytokine Res. 17:503-524.
18. Der, S. D., Y.-L. Yang, C. Weissman, and B. R. G. Williams. 1997. A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis. Proc. Natl. Acad. Sci. USA 94:3279-3283.
19. Di Bisceglie, A. M. 1995. Hepatitis C and hepatocellular carcinoma. Semin. Liver Dis. 15:64-69.
20. Domingo, E., E. Baranowski, C. M. Ruiz-Jarabo, A. M. Martin-Hernandez, J. C. Saiz, and C. Escarmis. 1998. Quasispecies structure and persistence of RNA viruses. Emerging Infect. Dis. 4:521-527.
21. Donzé, O., R. Jagus, A. E. Koromilas, J. W. B. Hershey, and N. Sonenberg. 1995. Abrogation of translation initiation factor eIF-2 phosphorylation causes malignant transformation of NIH 3T3 cells. EMBO J. 14:3828-3834.
22. Duarte, E. A., I. S. Novella, S. C. Weaver, E. Domingo, S. Wain-Hobson, D. K. Clarke, A. Moya, S. F. Elena, J. C. de la Torre, and J. J. Holland. 1994. RNA virus quasispecies: significance for viral disease and epidemiology. Infect. Agents Dis. 3:201-214.
23. Enomoto, N., I. Sakuma, Y. Asahina, M. Kurosaki, T. Murakami, C. Yamamoto, Y. Ogura, N. Izumi, F. Maruno, and C. Sato. 1996. Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N. Engl. J. Med. 334:77-81.
24. Enomoto, N., I. Sakuma, Y. Asahina, M. Kurosaki, T. Murankami, C. Yamamoto, N. Izumi, F. Marumo, and C. Sato. 1995. Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1b. J. Clin. Investig. 96:224-230.
25. Fernadez, I., G. Castellano, M. J. Domingo, A. Fuertes, F. Colina, F. Canga, F. J. DelaCruz, A. G. DelaCamara, and J. A. Solis. 1997. Influence of viral genotype and the level of viremia on the severity of liver injury and the response to interferon therapy. Scand. J. Gastroenterol. 32:7-76.
26. Fukuma, T., N. Enomoto, F. Marumo, and C. Sato. 1998. Mutations in the interferon-sensitivity determining region of hepatitis C virus and transcriptional activity of the nonstructural region 5A protein. Hepatology 28:1147-1153.
27. Gale, M., Jr., C. Zhou, E. J. Firpo, M. G. Katze, A. Rudendsky, and B. R. Franza, Jr. 1999. Unpublished observations.
28. rIPK. Mol. Cell. Biol. 18:859-871.
29. Gale, M., Jr., C. M. Blakely, B. Kwieciszewski, S.-L. Tan, M. Dossett, M. J. Korth, S. J. Polyak, D. R. Gretch, and M. G. Katze. 1998. Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol. Cell. Biol. 18:5208-5218.
30. Gale, M., Jr., and M. G. Katze. 1998. Molecular mechanisms of interferon resistance mediated by viral-directed inhibition of PKR, the interferon-induced protein kinase. Pharmacol. Ther. 78:29-46.
31. Gale, M., Jr., M. J. Korth, and M. G. Katze. 1998. Repression of the PKR protein kinase by hepatitis C virus: a potential mechanism for interferon resistance. Clin. Diagn. Virol. 10:157-162.
32. Gale, M., Jr., M. J. Korth, N. M. Tang, S.-L. Tan, D. A. Hopkins, T. E. Dever, S. J. Polyak, D. R. Gretch, and M. G. Katze. 1997. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology 230:217-227.
33. Haruna, Y., N. Hayashi, T. Kamada, P. Hytiroglou, S. N. Thung, and M. A. Gerber. 1994. Expression of hepatitis C virus in hepatocellular carcinoma. Cancer 73:2253-2258.
34. Herion, D., and J. Hoofnagle. 1997. The interferon sensitivity determining region: all hepatitis C virus isolates are not the same. Hepatology 25:769-771.
35. Hofgärtner, W. T., S. J. Polyak, D. Sullivan, R. L. Jr. Carithers, and D. R. Gretch. 1997. Mutations in the NS5A gene of hepatitis C virus in North American patients infected with HCV genotype 1a or 1b. J. Med. Virol. 53:118-126.
36. Hoofnagle, J. H. 1994. Therapy of acute and chronic viral hepatitis. Adv. Intern. Med. 39:241-275.
37. Iino, S., K. Hino, and K. Yasuda. 1994. Current state of interferon therapy for chronic hepatitis C. Intervirology 37:87-100.
38. Kato, N., M. Hijikata, Y. Ootsuyama, M. Nakagawa, S. Ohkoshi, T. Sugimura, and K. Shimotohno. 1990. Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis. Proc. Natl. Acad. Sci. USA 87:9524-9528.
39. Kato, N., K. H. Lan, S. K. Ono-Nita, Y. Shiratori, and M. Omata. 1997. Hepatitis C virus nonstructural region 5A protein is a potent transcriptional activator. J. Virol. 71:8856-8859.
40. Katze, M. G. 1995. Regulation of the interferon-induced PKR: can viruses cope? Trends Microbiol. 3:75-78.
41. Khorsi, H., S. Castelain, A. Wyseur, J. Izopet, V. Canva, A. Rombout, D. Capron, J.-P. Capron, F. Lunel, L. Stuyver, and G. Duverlie. 1997. Mutations of hepatitis C virus 1b NS5A 2209-2248 amino acid sequence do not predict the response to recombinant interferon-alpha therapy in French patients. J. Hepatol. 27:72-77.
42. Kirchhoff, S., A. E. Koromilas, F. Schaper, M. Grashof, N. Sonenberg, and H. Hauser. 1995. IRF-1 induced cell growth inhibition and interferon induction requires the activity of the protein kinase PKR. Oncogene 11:439-445.
43. Koff, R. S. 1997. Therapy in chronic hepatitis C: say goodbye to the 6-month interferon regimen. Am. J. Gastroenterol. 91:2072-2074.
44. Koromilas, A. E., S. Roy, G. N. Barber, M. G. Katze, and N. Sonenberg. 1992. Malignant transformation by a mutant of the IFN-inducible dsRNA-dependent protein kinase. Science 257:1685-1689.
45. Kumar, A., J. Haque, J. Lacoste, J. Hiscott, and B. R. G. Williams. 1994. Double-stranded RNA-dependent protein kinase activates transcription factor NF-κB by phosphorylating IκB. Proc. Natl. Acad. Sci. USA 91:6288-6292.
46. Kumar, A., Y.-L. Yang, V. Flati, S. Der, S. Kadereit, A. Deb, J. Haque, L. Reis, C. Weissmann, and B. R. G. Williams. 1997. Deficient cytokine signaling in mouse embryo fibroblasts with a targeted deletion in the PKR gene: role of IRF-I and NF-κB. EMBO J. 16:406-416.
47. Kurosaki, M., N. Enomoto, T. Murakami, I. Sakuma, Y. Asahina, C. Yamamoto, T. Ikeda, S. Tozuka, N. Izumi, F. Marumo, and C. Sato. 1997. Analysis of genotypes and amino acid residues 2209 to 2248 of the NS5A region of hepatitis C virus in relation to the response to interferon-β therapy. Hepatology 25:750-753.
48. r protein and their use for the detection of double-stranded RNA dependent protein kinase in human cells. Proc. Natl. Acad. Sci. USA 82:4341-4345.
49. Lee, S. B., R. Bablanian, and M. Esteban. 1996. Regulated expression of the interferon-induced protein kinase p68 (PKR) by vaccinia virus recombinants inhibits the replication of vesicular stomatitis virus but not that of poliovirus. J. Interferon Cytokine Res. 16:1073-1078.
50. Lee, S. Y., W. M. Lui, and J. V. Maizel. 1998. Phylogenetic evidence for the improved RNA higher-order structure in internal ribosome entry sequences of HCV and pestiviruses. Virus Genes 17:279-295.
51. Lee, W. M., K. R. Ready, M. J. Tong, M. Black, D. J. van Leeuwen, F. B. Hooinger, K. D. Mullem, N. Pimstone, D. Albert, S. Gardner, and the Consensus Interferon Study Group. 1998. Early hepatitis C virus-RNA responses predict interferon treatment outcomes in chronic hepatitis C. Hepatology 28:1411-1415.
52. 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. 66:3225-3229.
53. Martinot-Peignoux, M., P. Marcellin, M. Pouteau, C. Castelnau, N. Boyer, M. Poliquin, C. Degott, I. Descombes, V. Le Breton, V. Milotova, J. P. Benhamou, and S. Erlinger. 1995. Pretreatment serum hepatitis C virus RNA levels and hepatitis C virus genotype are the main and independent prognostic factors of sustained response to interferon alfa therapy in chronic hepatitis C. Hepatology 22:1050-1056.
54. Matsumoto, M., T.-Y. Hsieh, N. Zhu, T. VanArsdale, S. B. Hwang, A. E. Gorbalenya, S.-Y. Lo, J.-H. Ou, C. F. Ware, and M. C. Lai. 1997. Hepatitis C virus core protein interacts with the cytoplasmic tail of the lymphotoxin-β receptor. J. Virol. 71:1301-1309.
55. McHutchison, J. G., S. C. Gordon, E. R. Schiff, M. L. Shiffman, W. M. Lee, Z. D. Goodman, M. H. Ling, S. Cort, and J. K. Albrecht, for the Interferon Interventional Therapy Group. 1998. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N. Engl. J. Med. 339:1485-1492.
56. Merrick, W. C., and J. W. B. Hershey. 1996. The pathway and mechanism of eukaryotic protein synthesis, p. 31-70. In J. Hershey, M. Mathews, and N. Sonenberg (ed.), Translational control. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.
57. Meurs, E., K. L. Chong, J. Galabru, N. Thomas, I. Kerr, B. R. G. Williams, and A. G. Hovanessian. 1990. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell 62:379-390.
58. Meurs, E. F., J. Galabru, G. N. Barber, M. G. Katze, and A. G. Hovanessian. 1993. Tumor suppressor function of the interferon-induced double-stranded RNA-activated protein kinase. Proc. Natl. Acad. Sci. USA 90:232-236.
59. Morisco, F., C. Tuccillo, G. Sessa, G. Brunasso, and N. Caporaso. 1998. Chronic hepatitis C long-term responders to human leukocyte interferon-alpha therapy: persistence of a sustained biochemical and virological response during 5 years of surveillance. Eur. J. Gastroenterol. Hepatol. 10: 399-403.
60. Neddermann, P., L. Tomei, C. Steinkühler, P. Gallinari, A. Tramontane, and R. De Francesco. 1997. The nonstructural proteins of the hepatitis C virus: structure and functions. Biol. Chem. 378:469-476.
61. Negro, F., and M. Levrero. 1998. Does hepatitis C virus replicate in cells of the hematopoetic lineage? Hepatology 28:261-264.
62. Nelson, D. R., and J. Y. N. Lau. 1999. Pathogenesis of chronic hepatitis C virus infection. Antiviral. Ther. 3:25-35.
63. Neumann, A. U., N. P. Lam, H. Dahari, D. R. Gretch, T. E. Wiley, T. J. Layden, and A. S. Perelson. 1999. Hepatitis C virus dynamic in vivo and the antiviral efficacy of interferon-α therapy. Science 282:103-107.
64. O'Brien, V. 1998. Viruses and apoptosis. J. Gen. Virol. 79:1833-1845.
65. Ohsawa, M., N. Shingu, H. Miwa, H. Yoshihara, M. Kubo, H. Tsukuma, H. Teshima, M. Hashimoto, and K. Aozasa. 1999. Risk of non-Hodgkin's lymphoma in patients with hepatitis C virus infection. Int. J. Cancer 80:237-239.
66. Okuda, K. 1998. Hepatitis C and hepatocellular carcinoma. J. Gastroenterol. Hepatol. 13:294-298.
67. Pawlotsky, J.-M., G. Germanidis, A. U. Neumann, M. Pellerin, P.-O. Frainais, and D. Dhumeaux. 1998. Interferon resistance of hepatitis C virus genotype 1b: relationship to nonstructural 5A gene quasispecies mutations. J. Virol. 72:2795-2805.
68. Polyak, S. J., D. Paschal, S. McArdla, M. Gale, Jr., D. Moradpour, and D. R. Gretch. 1999. Characterization of the effects of hepatitis C virus nonstructural 5A protein expression in human cell lines and on interferon-sensitive virus replication. Hepatology 29:1262-1270.
69. Ray, R. B., R. Steele, K. Meyer, and R. Ray. 1998. Hepatitis C virus core protein represses p21(WAF1/Cip1/Sid1) promoter activity. Gene 208:331-336.
70. Ray, R. B., L. M. Lagging, K. Meyer, and R. Ray. 1996. Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. J. Virol. 70:4438-4443.
71. Ray, R. B., R. Steele, K. Meyer, and R. Ray. 1997. Transcriptional repression of p53 promoter by hepatitis C virus core protein. J. Biol. Chem. 272:10983-10986.
72. Ruggieri, A., T. Harada, Y. Matsuura, and T. Miyamura. 1997. Sensitization to Fas-mediated apoptosis by hepatitis C virus core protein. Virology 229: 68-76.
73. Saito, I., T. Miyamura, A. Ohbayashi, H. Harada, T. Katayama, S. Kikuchi, Y. Watanabe, S. Koi, et al. 1990. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc. Natl. Acad. Sci. USA 87:6547-6549.
74. Sakamuro, D., T. Furukawa, and T. Takegami. 1995. Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells. J. Virol. 69:3893-3896.
75. Savinova, O., and R. Jagus. 1997. Use of vertical slab isoelectric focusing and immunoblotting to evaluate steady-state phosphorylation of eIF-2α in cultured cells. Methods Companion Methods Enzymol. 11:419-425.
76. Sen, G. C., and R. M. Ransohoff. 1993. Interferon-induced antiviral actions and their regulation. Adv. Virus Res. 42:57-102.
77. Sharara, A. I., C. M. Hunt, and J. D. Hamilton. 1996. Hepatitis C. Ann. Intern. Med. 125:658-668.
78. Shitnada, A., G. Shiota, H. Miyatya, T. Kamahora, H. Kawasaki, K. Shiraki, S. Hino, and T. Terada. 1998. Aberrant expression of double-stranded RNA-dependent protein kinase in hepatocytes of chronic hepatitis and differentiated hepatocellular carcinoma. Cancer Res. 58:4434-4438.
79. Shors, S. T., E. Beattie, K. Paoletti, J. Tartaglia, and B. L. Jacobs. 1998. Role of the vaccinia virus E3L and K3L gene products in rescue of VSV and EMCV from the effects of IFN-alpha. J. Interferon Cytokine Res. 18:721-729.
80. Srivastava, S. P., M. V. Davies, and R. J. Kaufman. 1995. Calcium depletion from the endoplasmic reticulum activates the double-stranded RNA-dependent protein kinase (PKR) to inhibit protein synthesis. J. Biol. Chem. 270: 16619-16624.
81. Srivastava, S. P., K. U. Kumar, and R. J. Kaufman. 1998. Phosphorylation of eukaryotic translation initiation factor 2 mediates apoptosis in response to activation of the double-stranded RNA-dependent protein kinase. J. Biol. Chem. 273:2416-2423.
82. Tan, S.-L., and M. G. Katze. The emerging role of the interferon-induced PKR protein kinase as an apoptotic effector: a new face of death? J. Interferon Cytokine Res., in press.
83. Tan, S.-L., H. Nakao, Y. He, V. Vijaysri, P. Neddermann, B. L. Jacobs, B. J. Mayer, and M. G. Katze. 1999. NS5A, a nonstructural protein of hepatitis C virus, binds growth factor receptor-bound protein 2 adaptor protein in a Src homology 3 domain/ligand-dependent manner and perturbs mitogenic signaling. Proc. Natl. Acad. Sci. USA 96:5533-5538.
84. Tang, N. M., C. Y. Ho, and M. G. Katze. 1996. The 58-kDa cellular inhibitor of the double stranded RNA-dependent protein kinase requires the tetratricopeptide repeat 6 and DnaJ motifs to stimulate protein synthesis in vivo. J. Biol. Chem. 271:28660-28666.
85. Teodoro, J. G., and P. E. Branton. 1997. Regulation of apoptosis by viral gene products. J. Virol. 71:1739-1746.
86. Trepo, C., P. Berthillon, and L. Vitvitski. 1998. HCV and lymphoproliferative diseases. Ann. Oncol. 9:469-470.
87. Yang, Y.-L., L. F. L. Reis, J. Pavlovic, A. Aguzzi, R. Schäfer, A. Kumar, B. R. G. Williams, M. Aguet, and C. Weissmann. 1995. Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J. 14:6095-6106.
88. You, L. R., and C. M. Chen. 1999. Hepatitis C virus core protein enhances NF-κB signal pathway triggering by lymphotoxin-beta receptor ligand and tumor necrosis factor alpha. J. Virol. 73:1672-1681.
89. Zamanian-Daryoush, M., S. D. Der, and B. R. G. Williams. 1999. Cell cycle regulation of the double stranded RNA activated protein kinase, PKR. Oncogene 17:315-326.
90. Zeuzem, S., J.-H. Lee, and W. K. Roth. 1997. Mutations in the nonstructural 5A gene of European hepatitis C virus isolates and response to interferon alfa. Hepatology 25:740-744.
91. Zhu, N., A. Khoshan, R. Schneider, M. Matsumoto, G. Dennert, C. F. Ware, and M. C. Lai. 1998. Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis. J. Virol. 72:3691-3697.