Hurdles to the Development of Effective HBV Immunotherapies and HCV Vaccines
Article Sidebar
Main Article Content
Abstract
Chronic infections with HBV and HCV continue to be major public health problems, with hundreds of millions of people infected worldwide; this is despite the availability of both an effective prophylactic HBV vaccine for more than 3 decades and potent direct antivirals for HBV and, more recently, HCV infection. Consequently, development of HBV immunotherapies and prophylactic HCV vaccines remains extremely urgent, but limited funding and significant gaps in our understanding of the correlates of immune protection pose serious hurdles for the development of novel immune-based interventions. Here we discuss immunological questions related to HBV and HCV, some shared and some pertinent to only 1 of the viruses, that should be addressed for the rational design of HBV immunotherapies and HCV vaccines.
Downloads
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
Pathogens and Immunity abides by Creative Commons BY 4.0:
http://creativecommons.org/licenses/by/4.0/
This license lets others distribute, remix, tweak, and build upon your work for any lawful purpose, even commercially, as long as they credit you for the original creation. This is the most accommodating of licenses offered. Recommended for maximum dissemination and use of licensed materials. The authors maintain copyright of their materal.
*Due to a template error on our pdfs, articles published from May 20, 2016 to June 24, 2022 incorrectly state the copyright is held by Pathogens and Immunity. Copyright of all articles is held by the authors of each article as noted in the above copyright policy.
References
1. WHO. Global Health Sector Strategy on Viral Hepatitis 2016-2021. Towards Ending Viral Hepatitis 2016 [updated June 2016]. WHO/HIV/2016.06]. Available from: http://www.who.int/hepatitis/strategy2016-2021/ghss-hep/en/ .
2. The Immunological basis for immunization series [Internet]. 2011. Available from: http://www.who.int/immunization/documents/ISBN_978_92_4_150475_1/en/ .
3. Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 2012;30(12):2212-9. PubMed PMID: 22273662. doi: 10.1016/j.vaccine.2011.12.116
4. Stephenne J. Contribution to hepatitis B prevention. Vaccine. 1992;10(13):900-3. PubMed PMID: 1471409.
5. Lok E-KTaAS. Epidemiology, transmission, and prevention of hepatitis B virus infection UptoDate2016 [updated February 2017; cited 2016]. Available from: https://www.uptodate.com/contents/epidemiology-transmission-and-prevention-of-hepatitis-b-virus-infection .
6. Perrillo R. Invited Commentary: Screening for hepatitis B in the immigrant population and individuals who are in need of immunosuppressive drug therapy. Proc (Bayl Univ Med Cent). 2015;28(4):443-4. PubMed PMID: 26424936. Pubmed Central PMCID: PMC4569219.
7. WHO. Immunization coverage. WHO, 2016 september 2016. Report No.
8. Infection IoMUCotPaCoVH. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. In: Colvin HM, Mitchell AE, editors. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Washington (DC)2010.
9. Farnik H, Zeuzem S. New antiviral therapies in the management of HCV infection. Antivir Ther. 2012;17(5):771-83. PubMed PMID: 22626842. doi: 10.3851/IMP2127
10. Graham CS, Swan T. A path to eradication of hepatitis C in low- and middle-income countries. Antiviral Res. 2015;119:89-96. PubMed PMID: 25615583. doi: 10.1016/j.antiviral.2015.01.004
11. Hesamizadeh K, Sharafi H, Rezaee-Zavareh MS, Behnava B, Alavian SM. Next Steps Toward Eradication of Hepatitis C in the Era of Direct Acting Antivirals. Hepat Mon. 2016;16(4):e37089. PubMed PMID: 27275164. Pubmed Central PMCID: PMC4893415. doi: 10.5812/hepatmon.37089
12. Scott N, McBryde E, Vickerman P, Martin NK, Stone J, Drummer H, Hellard M. The role of a hepatitis C virus vaccine: modelling the benefits alongside direct-acting antiviral treatments. BMC Med. 2015;13:198. PubMed PMID: 26289050. Pubmed Central PMCID: PMC4546023. doi:
13. Suryaprasad AG, White JZ, Xu F, Eichler BA, Hamilton J, Patel A, Hamdounia SB, Church DR, Barton K, Fisher C, Macomber K, Stanley M, Guilfoyle SM, Sweet K, Liu S, Iqbal K, Tohme R, Sharapov U, Kupronis BA, Ward JW, Holmberg SD. Emerging epidemic of hepatitis C virus infections among young nonurban persons who inject drugs in the United States, 2006-2012. Clin Infect Dis. 2014;59(10):1411-9. PubMed PMID: 25114031. doi: 10.1093/cid/ciu643
14. Centers for Disease C, Prevention. Hepatitis C virus infection among adolescents and young adults:Massachusetts, 2002-2009. MMWR Morb Mortal Wkly Rep. 2011;60(17):537-41. PubMed PMID: 21544042.
15. Klevens RM, Hu DJ, Jiles R, Holmberg SD. Evolving epidemiology of hepatitis C virus in the United States. Clin Infect Dis. 2012;55 Suppl 1:S3-9. PubMed PMID: 22715211. doi: 10.1093/cid/cis393
16. Centers for Disease C, Prevention. Notes from the field : hepatitis C virus infections among young adults--rural Wisconsin, 2010. MMWR Morb Mortal Wkly Rep. 2012;61(19):358. PubMed PMID: 22592276.
17. Kim AY, Onofrey S, Church DR. An epidemiologic update on hepatitis C infection in persons living with or at risk of HIV infection. J Infect Dis. 2013;207 Suppl 1:S1-6. PubMed PMID: 23390299. Pubmed Central PMCID: PMC3565593. doi: 10.1093/infdis/jis927
18. NIH. Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC) 2016 [2017]. Available from: https://report.nih.gov/categorical_spending.aspx
19. Rosen HR. "Hep C, where art thou": What are the remaining (fundable) questions in hepatitis C virus research? Hepatology. 2017;65(1):341-9. PubMed PMID: 27640881. doi: 10.1002/hep.28848
20. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001;345(1):41-52. PubMed PMID: 11439948.
21. Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, Koziel MJ. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001;33(4):562-9. PubMed PMID: 11462196.
22. Ganem D, Prince AM. Hepatitis B virus infection--natural history and clinical consequences. N Engl J Med. 2004;350(11):1118-29. PubMed PMID: 15014185. doi: 10.1056/NEJMra031087
23. Chen SL, Morgan TR. The natural history of hepatitis C virus (HCV) infection. Int J Med Sci. 2006;3(2):47-52. PubMed PMID: 16614742. Pubmed Central PMCID: PMC1415841.
24. Wu JF, Chang MH. Natural history of chronic hepatitis B virus infection from infancy to adult life - the mechanism of inflammation triggering and long-term impacts. J Biomed Sci. 2015;22:92. PubMed PMID: 26487087. Pubmed Central PMCID: PMC4618235. doi: 10.1186/s12929-015-0199-y
25. Chou HH, Chien WH, Wu LL, Cheng CH, Chung CH, Horng JH, Ni YH, Tseng HT, Wu D, Lu X, Wang HY, Chen PJ, Chen DS. Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota. Proc Natl Acad Sci U S A. 2015;112(7):2175-80. PubMed PMID: 25646429. Pubmed Central PMCID: PMC4343154. doi: 10.1073/pnas.1424775112
26. Taylor BC, Yuan JM, Shamliyan TA, Shaukat A, Kane RL, Wilt TJ. Clinical outcomes in adults with chronic hepatitis B in association with patient and viral characteristics: A systematic review of evidence. Hepatology. 2009;49(5 Suppl):S85-95. PubMed PMID: 19399797. doi: 10.1002/hep.22929
27. Liang TJ. Hepatitis B: the virus and disease. Hepatology. 2009;49(5 Suppl):S13-21. PubMed PMID: 19399811. Pubmed Central PMCID: PMC2809016. doi: 10.1002/hep.22881
28. Milich DR, Jones JE, Hughes JL, Price J, Raney AK, McLachlan A. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Proc Natl Acad Sci U S A. 1990;87(17):6599-603. PubMed PMID: 2395863. Pubmed Central PMCID: PMC54584.
29. Milich DR, Jones J, Hughes J, Maruyama T. Role of T-cell tolerance in the persistence of hepatitis B virus infection. J Immunother Emphasis Tumor Immunol. 1993;14(3):226-33. PubMed PMID: 8297904.
30. Tian Y, Kuo CF, Akbari O, Ou JH. Maternal-Derived Hepatitis B Virus e Antigen Alters Macrophage Function in Offspring to Drive Viral Persistence after Vertical Transmission. Immunity. 2016;44(5):1204-14. PubMed PMID: 27156385. Pubmed Central PMCID: PMC4871724. doi: 10.1016/j.immuni.2016.04.008
31. Bertoletti A, Kennedy PT. The immune tolerant phase of chronic HBV infection: new perspectives on an old concept. Cell Mol Immunol. 2015;12(3):258-63. PubMed PMID: 25176526. Pubmed Central PMCID: PMC4654319. doi: 10.1038/cmi.2014.79
32. Publicover J, Goodsell A, Nishimura S, Vilarinho S, Wang ZE, Avanesyan L, Spolski R, Leonard WJ, Cooper S, Baron JL. IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B. J Clin Invest. 2011;121(3):1154-62. PubMed PMID: 21393863. Pubmed Central PMCID: PMC3049376. doi: 10.1172/JCI44198
33. Tran TT. Immune tolerant hepatitis B: a clinical dilemma. Gastroenterology & hepatology. 2011;7(8):511-6. PubMed PMID: 22298987. Pubmed Central PMCID: 3264935.
34. Centers for Disease C. Immunization Schedules for Infants and Children. 2017.
35. Shalek AK, Satija R, Shuga J, Trombetta JJ, Gennert D, Lu D, Chen P, Gertner RS, Gaublomme JT, Yosef N, Schwartz S, Fowler B, Weaver S, Wang J, Wang X, Ding R, Raychowdhury R, Friedman N, Hacohen N, Park H, May AP, Regev A. Single-cell RNA-seq reveals dynamic paracrine control of cellular variation. Nature. 2014;510(7505):363-9. PubMed PMID: 24919153. Pubmed Central PMCID: 4193940. doi: 10.1038/nature13437
36. Lokhande MU, Thimme R, Klenerman P, Semmo N. Methodologies for the Analysis of HCV-Specific CD4(+) T Cells. Frontiers in immunology. 2015;6:57. PubMed PMID: 25767470. Pubmed Central PMCID: 4341113. doi: 10.3389/fimmu.2015.00057
37. Wright TL, Lau JY. Clinical aspects of hepatitis B virus infection. Lancet. 1993;342(8883):1340-4. PubMed PMID: 7694023.
38. Pan CQ, Zhang JX. Natural History and Clinical Consequences of Hepatitis B Virus Infection. International journal of medical sciences. 2005;2(1):36-40. PubMed PMID: 15968338. Pubmed Central PMCID: 1142223.
39. Rehermann B, Bertoletti A. Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections. Hepatology. 2015;61(2):712-21. PubMed PMID: 25048716. Pubmed Central PMCID: PMC4575407. doi: 10.1002/hep.27323
40. Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med. 1996;2(10):1104-8. PubMed PMID: 8837608.
41. Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology. 1991;100(1):182-8. PubMed PMID: 1983820.
42. Tsutsumi Y, Yamamoto Y, Ito S, Ohigashi H, Shiratori S, Naruse H, Teshima T. Hepatitis B virus reactivation with a rituximab-containing regimen. World journal of hepatology. 2015;7(21):2344-51. PubMed PMID: 26413224. Pubmed Central PMCID: PMC4577642. doi: 10.4254/wjh.v7.i21.2344
43. Nassal M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut. 2015;64(12):1972-84. PubMed PMID: 26048673. doi: 10.1136/gutjnl-2015-309809
44. Morikawa K, Shimazaki T, Takeda R, Izumi T, Umumura M, Sakamoto N. Hepatitis B: progress in understanding chronicity, the innate immune response, and cccDNA protection. Ann Transl Med. 2016;4(18):337. PubMed PMID: 27761441. Pubmed Central PMCID: PMC5066049. doi: 10.21037/atm.2016.08.54
45. Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK, Wey K, Royston I, Davis T, Levy R. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood. 1997;90(6):2188-95. PubMed PMID: 9310469.
46. Misumi I, Whitmire JK. B cell depletion curtails CD4+ T cell memory and reduces protection against disseminating virus infection. J Immunol. 2014;192(4):1597-608. PubMed PMID: 24453250. Pubmed Central PMCID: PMC3925510. doi: 10.4049/jimmunol.1302661
47. Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH, Chisari FV. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol. 2003;77(1):68-76. PubMed PMID: 12477811. Pubmed Central PMCID: 140637.
48. Asabe S, Wieland SF, Chattopadhyay PK, Roederer M, Engle RE, Purcell RH, Chisari FV. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol. 2009;83(19):9652-62. PubMed PMID: 19625407. Pubmed Central PMCID: PMC2748002. doi: 10.1128/JVI.00867-09
49. Penna A, Artini M, Cavalli A, Levrero M, Bertoletti A, Pilli M, Chisari FV, Rehermann B, Del Prete G, Fiaccadori F, Ferrari C. Long-lasting memory T cell responses following self-limited acute hepatitis B. J Clin Invest. 1996;98(5):1185-94. PubMed PMID: 8787682. Pubmed Central PMCID: PMC507541. doi: 10.1172/JCI118902
50. Rehermann B, Lau D, Hoofnagle JH, Chisari FV. Cytotoxic T lymphocyte responsiveness after resolution of chronic hepatitis B virus infection. J Clin Invest. 1996;97(7):1655-65. PubMed PMID: 8601631. Pubmed Central PMCID: PMC507230. doi: 10.1172/JCI118592
51. Boni C, Fisicaro P, Valdatta C, Amadei B, Di Vincenzo P, Giuberti T, Laccabue D, Zerbini A, Cavalli A, Missale G, Bertoletti A, Ferrari C. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol. 2007;81(8):4215-25. PubMed PMID: 17287266. Pubmed Central PMCID: 1866111. doi: 10.1128/JVI.02844-06
52. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 2005;5(3):215-29. PubMed PMID: 15738952. doi: 10.1038/nri1573
53. Hwang JP, Barbo AG, Perrillo RP. Hepatitis B reactivation during cancer chemotherapy: an international survey of the membership of the American Association for the Study of Liver Diseases. J Viral Hepat. 2015;22(3):346-52. PubMed PMID: 25220947. Pubmed Central PMCID: PMC4833504. doi: 10.1111/jvh.12305
54. Totani H, Kusumoto S, Ishida T, Masuda A, Yoshida T, Ito A, Ri M, Komatsu H, Murakami S, Mizokami M, Ueda R, Niimi A, Inagaki H, Tanaka Y, Iida S. Reactivation of hepatitis B virus (HBV) infection in adult T-cell leukemia-lymphoma patients with resolved HBV infection following systemic chemotherapy. Int J Hematol. 2015;101(4):398-404. PubMed PMID: 25633779. doi: 10.1007/s12185-015-1750-z
55. Palmore TN, Shah NL, Loomba R, Borg BB, Lopatin U, Feld JJ, Khokhar F, Lutchman G, Kleiner DE, Young NS, Childs R, Barrett AJ, Liang TJ, Hoofnagle JH, Heller T. Reactivation of hepatitis B with reappearance of hepatitis B surface antigen after chemotherapy and immunosuppression. Clin Gastroenterol Hepatol. 2009;7(10):1130-7. PubMed PMID: 19577007. Pubmed Central PMCID: PMC2779698. doi: 10.1016/j.cgh.2009.06.027
56. Shin EC, Sung PS, Park SH. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol. 2016;16(8):509-23. PubMed PMID: 27374637. doi: 10.1038/nri.2016.69
57. Wu JF, Tsai WY, Hsu HY, Ni YH, Chen HL, Tsuei DJ, Chang MH. Effect of puberty onset on spontaneous hepatitis B virus e antigen seroconversion in men. Gastroenterology. 2010;138(3):942-8 e1. PubMed PMID: 19962986. doi: 10.1053/j.gastro.2009.11.051
58. Wu JF, Tsai WY, Tung YC, Chen HL, Ni YH, Hsu HY, Chang MH. Effect of menarche onset on the clinical course in females with chronic hepatitis B virus infection. J Pediatr. 2014;165(3):534-8. PubMed PMID: 24973292. doi: 10.1016/j.jpeds.2014.05.049
59. Hohler T, Gerken G, Notghi A, Lubjuhn R, Taheri H, Protzer U, Lohr HF, Schneider PM, Meyer zum Buschenfelde KH, Rittner C. HLA-DRB1*1301 and *1302 protect against chronic hepatitis B. J Hepatol. 1997;26(3):503-7. PubMed PMID: 9075656.
60. Ahn SH, Han KH, Park JY, Lee CK, Kang SW, Chon CY, Kim YS, Park K, Kim DK, Moon YM. Association between hepatitis B virus infection and HLA-DR type in Korea. Hepatology. 2000;31(6):1371-3. PubMed PMID: 10827165. doi: 10.1053/jhep.2000.7988
61. Almarri A, Batchelor JR. HLA and hepatitis B infection. Lancet. 1994;344(8931):1194-5. PubMed PMID: 7934542.
62. Wu JF, Ni YH, Lin YT, Lee TJ, Hsu SH, Chen HL, Tsuei DJ, Hsu HY, Chang MH. Human interleukin-10 genotypes are associated with different precore/core gene mutation patterns in children with chronic hepatitis B virus infection. J Pediatr. 2011;158(5):808-13. PubMed PMID: 21168854. doi: 10.1016/j.jpeds.2010.11.015
63. Wu JF, Wu TC, Chen CH, Ni YH, Chen HL, Hsu HY, Chang MH. Serum levels of interleukin-10 and interleukin-12 predict early, spontaneous hepatitis B virus e antigen seroconversion. Gastroenterology. 2010;138(1):165-72 e1-3. PubMed PMID: 19782084. doi: 10.1053/j.gastro.2009.09.018
64. Wahle RC, Perez RM, Pereira PF, Oliveira EM, Emori CT, Uehara SN, Silva IS, Silva AE, Ferraz ML. Hepatitis B virus reactivation after treatment for hepatitis C in hemodialysis patients with HBV/HCV coinfection. Braz J Infect Dis. 2015;19(5):533-7. PubMed PMID: 25997784. doi: 10.1016/j.bjid.2015.04.003
65. Loomba R, Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies and future directions. Gastroenterology. 2017. PubMed PMID: 28219691. doi: 10.1053/j.gastro.2017.02.009
66. Zhang Z, Jin B, Zhang JY, Xu B, Wang H, Shi M, Wherry EJ, Lau GK, Wang FS. Dynamic decrease in PD-1 expression correlates with HBV-specific memory CD8 T-cell development in acute self-limited hepatitis B patients. J Hepatol. 2009;50(6):1163-73. PubMed PMID: 19395117. doi: 10.1016/j.jhep.2009.01.026
67. de Niet A, Stelma F, Jansen L, Sinnige MJ, Remmerswaal EB, Takkenberg RB, Kootstra NA, Reesink HW, van Lier RA, van Leeuwen EM. Restoration of T cell function in chronic hepatitis B patients upon treatment with interferon based combination therapy. J Hepatol. 2016;64(3):539-46. PubMed PMID: 26505119. doi: 10.1016/j.jhep.2015.10.013
68. Godon O, Fontaine H, Kahi S, Meritet JF, Scott-Algara D, Pol S, Michel ML, Bourgine M, group AHs. Immunological and Antiviral Responses After Therapeutic DNA Immunization in Chronic Hepatitis B Patients Efficiently Treated by Analogues. Mol Ther. 2014;22(3):675-84. PubMed PMID: 28141993. doi: 10.1038/mt.2013.274
69. Mandai M. PD-1/PD-L1 blockage in cancer treatment-from basic research to clinical application. Int J Clin Oncol. 2016;21(3):447. PubMed PMID: 26968586. doi: 10.1007/s10147-016-0969-x
70. Bersanelli M, Buti S. From targeting the tumor to targeting the immune system: Transversal challenges in oncology with the inhibition of the PD-1/PD-L1 axis. World J Clin Oncol. 2017;8(1):37-53. PubMed PMID: 28246584. Pubmed Central PMCID: PMC5309713. doi: 10.5306/wjco.v8.i1.37
71. Gardiner D, Lalezari J, Lawitz E, DiMicco M, Ghalib R, Reddy KR, Chang KM, Sulkowski M, Marro SO, Anderson J, He B, Kansra V, McPhee F, Wind-Rotolo M, Grasela D, Selby M, Korman AJ, Lowy I. A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection. PLoS One. 2013;8(5):e63818. PubMed PMID: 23717490. Pubmed Central PMCID: 3661719. doi: 10.1371/journal.pone.0063818
72. Fuertes Marraco SA, Neubert NJ, Verdeil G, Speiser DE. Inhibitory Receptors Beyond T Cell Exhaustion. Front Immunol. 2015;6:310. PubMed PMID: 26167163. Pubmed Central PMCID: PMC4481276. doi: 10.3389/fimmu.2015.00310
73. Zarour HM. Reversing T-cell Dysfunction and Exhaustion in Cancer. Clin Cancer Res. 2016;22(8):1856-64. PubMed PMID: 27084739. Pubmed Central PMCID: PMC4872712. doi: 10.1158/1078-0432.CCR-15-1849
74. Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity. 2016;44(5):989-1004. PubMed PMID: 27192565. Pubmed Central PMCID: PMC4942846. doi: 10.1016/j.immuni.2016.05.001
75. Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends in immunology. 2015;36(4):265-76. PubMed PMID: 25797516. Pubmed Central PMCID: 4393798. doi: 10.1016/j.it.2015.02.008
76. Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, Drake AM, Chen Z, Sen DR, Kurachi M, Barnitz RA, Bartman C, Bengsch B, Huang AC, Schenkel JM, Vahedi G, Haining WN, Berger SL, Wherry EJ. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science. 2016;354(6316):1160-5. PubMed PMID: 27789795. doi: 10.1126/science.aaf2807
77. Sen DR, Kaminski J, Barnitz RA, Kurachi M, Gerdemann U, Yates KB, Tsao HW, Godec J, LaFleur MW, Brown FD, Tonnerre P, Chung RT, Tully DC, Allen TM, Frahm N, Lauer GM, Wherry EJ, Yosef N, Haining WN. The epigenetic landscape of T cell exhaustion. Science. 2016;354(6316):1165-9. PubMed PMID: 27789799. doi: 10.1126/science.aae0491
78. Osburn WO, Fisher BE, Dowd KA, Urban G, Liu L, Ray SC, Thomas DL, Cox AL. Spontaneous control of primary hepatitis C virus infection and immunity against persistent reinfection. Gastroenterology. 2010;138(1):315-24. PubMed PMID: 19782080. Pubmed Central PMCID: 2889495. S0016-5085(09)01658-8 [pii]. doi: 10.1053/j.gastro.2009.09.017
79. Mehta SH, Cox A, Hoover DR, Wang XH, Mao Q, Ray S, Strathdee SA, Vlahov D, Thomas DL. Protection against persistence of hepatitis C. Lancet. 2002;359(9316):1478-83. PubMed PMID: 11988247.
80. Simmonds P. Genetic diversity and evolution of hepatitis C virus--15 years on. J Gen Virol. 2004;85(Pt 11):3173-88. PubMed PMID: 15483230.
81. Klenerman P, Fleming V, Barnes E. What are the prospects for controlling hepatitis C? PLoS Med. 2009;6(6):e1000096. PubMed PMID: 19529757. Pubmed Central PMCID: PMC2688087. doi: 10.1371/journal.pmed.1000096
82. Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, Perelson AS. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science. 1998;282(5386):103-7.
83. Smith DB, Bukh J, Kuiken C, Muerhoff AS, Rice CM, Stapleton JT, Simmonds P. Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource. Hepatology. 2014;59(1):318-27. PubMed PMID: 24115039. Pubmed Central PMCID: PMC4063340. doi: 10.1002/hep.26744
84. Ray SC, Arthur RR, Carella A, Bukh J, Thomas DL. Genetic epidemiology of hepatitis C virus throughout Egypt. J Infect Dis. 2000;182(3):698-707. PubMed PMID: 10950762. doi: 10.1086/315786
85. Cox AL, Mosbruger T, Mao Q, Liu Z, Wang XH, Yang HC, Sidney J, Sette A, Pardoll D, Thomas DL, Ray SC. Cellular immune selection with hepatitis C virus persistence in humans. J Exp Med. 2005;201(11):1741-52. PubMed PMID: 15939790.
86. Ray SC, Fanning L, Wang XH, Netski DM, Kenny-Walsh E, Thomas DL. Divergent and convergent evolution after a common-source outbreak of hepatitis C virus. J Exp Med. 2005;201(11):1753-9. PubMed PMID: 15939791. Pubmed Central PMCID: PMC2213258. doi: 10.1084/jem.20050122
87. Theiler J, Yoon H, Yusim K, Picker LJ, Fruh K, Korber B. Epigraph: A Vaccine Design Tool Applied to an HIV Therapeutic Vaccine and a Pan-Filovirus Vaccine. Sci Rep. 2016;6:33987. PubMed PMID: 27703185. Pubmed Central PMCID: PMC5050445 (PCT/US15/54067) on "HIV Vaccines Comprising One or More Population Episensus Antigens." Authors LJP and KF have a significant financial interest in TomegaVax Inc., a company that may have a commercial interest in the results of this research and technology. This potential individual and institutional conflict of interest has been reviewed and managed by OHSU. doi: 10.1038/srep33987
88. Barouch DH, O'Brien KL, Simmons NL, King SL, Abbink P, Maxfield LF, Sun YH, La Porte A, Riggs AM, Lynch DM, Clark SL, Backus K, Perry JR, Seaman MS, Carville A, Mansfield KG, Szinger JJ, Fischer W, Muldoon M, Korber B. Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys. Nat Med. 2010;16(3):319-23. PubMed PMID: 20173752. Pubmed Central PMCID: PMC2834868. doi: 10.1038/nm.2089
89. Swadling L, Halliday J, Kelly C, Brown A, Capone S, Ansari MA, Bonsall D, Richardson R, Hartnell F, Collier J, Ammendola V, Del Sorbo M, Von Delft A, Traboni C, Hill AV, Colloca S, Nicosia A, Cortese R, Klenerman P, Folgori A, Barnes E. Highly-Immunogenic Virally-Vectored T-cell Vaccines Cannot Overcome Subversion of the T-cell Response by HCV during Chronic Infection. Vaccines (Basel). 2016;4(3). PubMed PMID: 27490575. Pubmed Central PMCID: PMC5041021. doi: 10.3390/vaccines4030027
90. Lavillette D, Morice Y, Germanidis G, Donot P, Soulier A, Pagkalos E, Sakellariou G, Intrator L, Bartosch B, Pawlotsky JM, Cosset FL. Human serum facilitates hepatitis C virus infection, and neutralizing responses inversely correlate with viral replication kinetics at the acute phase of hepatitis C virus infection. J Virol. 2005;79(10):6023-34. PubMed PMID: 15857988. Pubmed Central PMCID: PMC1091689. doi: 10.1128/JVI.79.10.6023-6034.2005
91. Pestka JM, Zeisel MB, Blaser E, Schurmann P, Bartosch B, Cosset FL, Patel AH, Meisel H, Baumert J, Viazov S, Rispeter K, Blum HE, Roggendorf M, Baumert TF. Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C. Proc Natl Acad Sci U S A. 2007;104(14):6025-30. PubMed PMID: 17392433. Pubmed Central PMCID: 1851610. doi: 10.1073/pnas.0607026104
92. Folgori A, Capone S, Ruggeri L, Meola A, Sporeno E, Ercole BB, Pezzanera M, Tafi R, Arcuri M, Fattori E, Lahm A, Luzzago A, Vitelli A, Colloca S, Cortese R, Nicosia A. A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees. Nat Med. 2006;12(2):190-7. PubMed PMID: 16462801. doi: 10.1038/nm1353
93. Prince AM, Brotman B, Lee DH, Pfahler W, Tricoche N, Andrus L, Shata MT. Protection against chronic hepatitis C virus infection after rechallenge with homologous, but not heterologous, genotypes in a chimpanzee model. J Infect Dis. 2005;192(10):1701-9. PubMed PMID: 16235167. doi: 10.1086/496889
94. Logvinoff C, Major ME, Oldach D, Heyward S, Talal A, Balfe P, Feinstone SM, Alter H, Rice CM, McKeating JA. Neutralizing antibody response during acute and chronic hepatitis C virus infection. Proc Natl Acad Sci U S A. 2004;101(27):10149-54. PubMed PMID: 15220475. Pubmed Central PMCID: PMC454180. doi: 10.1073/pnas.0403519101
95. Timm J, Roggendorf M. Sequence diversity of hepatitis C virus: implications for immune control and therapy. World J Gastroenterol. 2007;13(36):4808-17. PubMed PMID: 17828811. Pubmed Central PMCID: PMC4611758.
96. Law M, Maruyama T, Lewis J, Giang E, Tarr AW, Stamataki Z, Gastaminza P, Chisari FV, Jones IM, Fox RI, Ball JK, McKeating JA, Kneteman NM, Burton DR. Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Nat Med. 2008;14(1):25-7. PubMed PMID: 18064037. doi: 10.1038/nm1698
97. Grakoui A, Shoukry NH, Woollard DJ, Han JH, Hanson HL, Ghrayeb J, Murthy KK, Rice CM, Walker CM. HCV persistence and immune evasion in the absence of memory T cell help. Science. 2003;302(5645):659-62. PubMed PMID: 14576438. doi: 10.1126/science.1088774
98. Gruner NH, Gerlach TJ, Jung MC, Diepolder HM, Schirren CA, Schraut WW, Hoffmann R, Zachoval R, Santantonio T, Cucchiarini M, Cerny A, Pape GR. Association of Hepatitis C Virus-Specific CD8+ T Cells with Viral Clearance in Acute Hepatitis C. J Infect Dis. 2000;181(5):1528-36.
99. Cox AL, Mosbruger T, Lauer GM, Pardoll D, Thomas DL, Ray SC. Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C. Hepatology. 2005;42(1):104-12. PubMed PMID: 15962289.
100. Gerlach JT, Diepolder HM, Jung MC, Gruener NH, Schraut WW, Zachoval R, Hoffmann R, Schirren CA, Santantonio T, Pape GR. Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C. Gastroenterology. 1999;117(4):933-41. PubMed PMID: 10500077.
101. Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV. Determinants of Viral Clearance and Persistence during Acute Hepatitis C Virus Infection. J Exp Med. 2001;194(10):1395-406. PubMed PMID: 11714747.
102. Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P, Robbins G, Phillips R, Klenerman P, Walker BD. Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med. 2000;191(9):1499-512.
103. Schulze Zur Wiesch J, Ciuffreda D, Lewis-Ximenez L, Kasprowicz V, Nolan BE, Streeck H, Aneja J, Reyor LL, Allen TM, Lohse AW, McGovern B, Chung RT, Kwok WW, Kim AY, Lauer GM. Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence. J Exp Med. 2012;209(1):61-75. PubMed PMID: 22213804. Pubmed Central PMCID: PMC3260872. doi: 10.1084/jem.20100388
104. Schulze zur Wiesch J, Lauer GM, Day CL, Kim AY, Ouchi K, Duncan JE, Wurcel AG, Timm J, Jones AM, Mothe B, Allen TM, McGovern B, Lewis-Ximenez L, Sidney J, Sette A, Chung RT, Walker BD. Broad repertoire of the CD4+ Th cell response in spontaneously controlled hepatitis C virus infection includes dominant and highly promiscuous epitopes. J Immunol. 2005;175(6):3603-13. PubMed PMID: 16148104.
105. Day CL, Lauer GM, Robbins GK, McGovern B, Wurcel AG, Gandhi RT, Chung RT, Walker BD. Broad specificity of virus-specific CD4+ T-helper-cell responses in resolved hepatitis C virus infection. J Virol. 2002;76(24):12584-95. PubMed PMID: 12438584.
106. McMahan RH, Golden-Mason L, Nishimura MI, McMahon BJ, Kemper M, Allen TM, Gretch DR, Rosen HR. Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. J Clin Invest. 2010;120(12):4546-57. PubMed PMID: 21084749. Pubmed Central PMCID: PMC2994339. doi: 10.1172/JCI43127
107. Urbani S, Amadei B, Tola D, Massari M, Schivazappa S, Missale G, Ferrari C. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol. 2006;80(22):11398-403. PubMed PMID: 16956940.
108. Osburn WO, Snider AE, Wells BL, Latanich R, Bailey JR, Thomas DL, Cox AL, Ray SC. Clearance of hepatitis C infection is associated with the early appearance of broad neutralizing antibody responses. Hepatology. 2014. PubMed PMID: 24425349. doi: 10.1002/hep.27013
109. Forthal D, Hope TJ, Alter G. New paradigms for functional HIV-specific nonneutralizing antibodies. Current opinion in HIV and AIDS. 2013;8(5):393-401. PubMed PMID: 23924999. Pubmed Central PMCID: PMC4097845. doi: 10.1097/COH.0b013e328363d486
110. Bogdanos DP, Gao B, Gershwin ME. Liver immunology. Compr Physiol. 2013;3(2):567-98. PubMed PMID: 23720323. Pubmed Central PMCID: PMC4201126. doi: 10.1002/cphy.c120011
111. Kroy DC, Ciuffreda D, Cooperrider JH, Tomlinson M, Hauck GD, Aneja J, Berger C, Wolski D, Carrington M, Wherry EJ, Chung RT, Tanabe KK, Elias N, Freeman GJ, de Kruyff RH, Misdraji J, Kim AY, Lauer GM. Liver environment and HCV replication affect human T-cell phenotype and expression of inhibitory receptors. Gastroenterology. 2014;146(2):550-61. PubMed PMID: 24148617. Pubmed Central PMCID: PMC3946973. doi: 10.1053/j.gastro.2013.10.022
112. Burke Schinkel SC, Carrasco-Medina L, Cooper CL, Crawley AM. Generalized Liver- and Blood-Derived CD8+ T-Cell Impairment in Response to Cytokines in Chronic Hepatitis C Virus Infection. PLoS One. 2016;11(6):e0157055. PubMed PMID: 27315061. Pubmed Central PMCID: PMC4912163. doi: 10.1371/journal.pone.0157055
113. Trombetta JJ, Gennert D, Lu D, Satija R, Shalek AK, Regev A. Preparation of Single-Cell RNA-Seq Libraries for Next Generation Sequencing. Curr Protoc Mol Biol. 2014;107:4 22 1-4 17. PubMed PMID: 24984854. doi: 10.1002/0471142727.mb0422s107
114. Shalek AK, Satija R, Adiconis X, Gertner RS, Gaublomme JT, Raychowdhury R, Schwartz S, Yosef N, Malboeuf C, Lu D, Trombetta JJ, Gennert D, Gnirke A, Goren A, Hacohen N, Levin JZ, Park H, Regev A. Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells. Nature. 2013;498(7453):236-40. PubMed PMID: 23685454. Pubmed Central PMCID: 3683364. doi: 10.1038/nature12172
115. Buscarini L, Fornari F, Bolondi L, Colombo P, Livraghi T, Magnolfi F, Rapaccini GL, Salmi A. Ultrasound-guided fine-needle biopsy of focal liver lesions: techniques, diagnostic accuracy and complications. A retrospective study on 2091 biopsies. J Hepatol. 1990;11(3):344-8. PubMed PMID: 2290025.
116. Fabbri G, Mastrorosa I, Vergori A, Mazzotta V, Pinnetti C, Grisetti S, Zaccarelli M, Ammassari A, Antinori A. Reactivation of occult HBV infection in an HIV/HCV Co-infected patient successfully treated with sofosbuvir/ledipasvir: a case report and review of the literature. BMC Infect Dis. 2017;17(1):182. PubMed PMID: 28249574. Pubmed Central PMCID: PMC5333431. doi: 10.1186/s12879-017-2287-y
117. Belperio PS, Shahoumian TA, Mole LA, Backus LI. Evaluation of Hepatitis B Reactivation among 62,920 Veterans treated with Oral Hepatitis C Antivirals. Hepatology. 2017. PubMed PMID: 28240789. doi: 10.1002/hep.29135