Hepatitis C Virus E1E2 Structure, Diversity, and Implications for Vaccine Development.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101509722 Publication Model: Electronic Cited Medium: Internet ISSN: 1999-4915 (Electronic) Linking ISSN: 19994915 NLM ISO Abbreviation: Viruses Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

Hepacivirus*/immunology ; Hepacivirus*/genetics ; Hepacivirus*/chemistry ; Viral Envelope Proteins*/immunology ; Viral Envelope Proteins*/chemistry ; Viral Envelope Proteins*/genetics ; Vaccine Development* ; Viral Hepatitis Vaccines*/immunology ; Hepatitis C*/prevention & control ; Hepatitis C*/immunology ; Hepatitis C*/virology; Humans ; Antibodies, Neutralizing/immunology ; Animals ; Hepatitis C Antibodies/immunology

Hepatitis C virus (HCV) is a major medical health burden and the leading cause of chronic liver disease and cancer worldwide. More than 58 million people are chronically infected with HCV, with 1.5 million new infections occurring each year. An effective HCV vaccine is a major public health and medical need as recognized by the World Health Organization. However, due to the high variability of the virus and its ability to escape the immune response, HCV rapidly accumulates mutations, making vaccine development a formidable challenge. An effective vaccine must elicit broadly neutralizing antibodies (bnAbs) in a consistent fashion. After decades of studies from basic research through clinical development, the antigen of choice is considered the E1E2 envelope glycoprotein due to conserved, broadly neutralizing antigenic domains located in the constituent subunits of E1, E2, and the E1E2 heterodimeric complex itself. The challenge has been elicitation of robust humoral and cellular responses leading to broad virus neutralization due to the relatively low immunogenicity of this antigen. In view of this challenge, structure-based vaccine design approaches to stabilize key antigenic domains have been hampered due to the lack of E1E2 atomic-level resolution structures to guide them. Another challenge has been the development of a delivery platform in which a multivalent form of the antigen can be presented in order to elicit a more robust anti-HCV immune response. Recent nanoparticle vaccines are gaining prominence in the field due to their ability to facilitate a controlled multivalent presentation and trafficking to lymph nodes, where they can interact with both the cellular and humoral components of the immune system. This review focuses on recent advances in understanding the E1E2 heterodimeric structure to facilitate a rational design approach and the potential for development of a multivalent nanoparticle-based HCV E1E2 vaccine. Both aspects are considered important in the development of an effective HCV vaccine that can effectively address viral diversity and escape.

J Clin Invest. 2022 Aug 1;132(15):. (PMID: 35588376)
Viruses. 2021 Jul 02;13(7):. (PMID: 34372503)
Vaccine. 2012 Dec 17;31(1):58-83. (PMID: 23142589)
Lancet. 2018 Jul 21;392(10143):232-243. (PMID: 30047376)
Elife. 2022 Jul 07;11:. (PMID: 35796426)
Nat Commun. 2023 Apr 8;14(1):1985. (PMID: 37031217)
Proc Natl Acad Sci U S A. 2023 Jan 24;120(4):e2208425120. (PMID: 36669119)
Science. 2022 Aug 5;377(6606):eabq0839. (PMID: 35857620)
J Gen Virol. 2007 Apr;88(Pt 4):1144-1148. (PMID: 17374757)
J Gen Virol. 2000 Oct;81(Pt 10):2451-2459. (PMID: 10993933)
Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9499-504. (PMID: 22623528)
Elife. 2020 Mar 03;9:. (PMID: 32125272)
Nature. 2016 Jul 7;535(7610):136-9. (PMID: 27309817)
Vaccines (Basel). 2020 Feb 17;8(1):. (PMID: 32079254)
Nanomedicine. 2019 Feb;16:69-78. (PMID: 30529790)
Front Immunol. 2019 Jan 24;10:22. (PMID: 30733717)
J Virol. 2022 Jun 22;96(12):e0052322. (PMID: 35612312)
J Infect Dis. 2018 Jul 13;218(4):633-644. (PMID: 29669026)
PLoS One. 2008 Sep 08;3(9):e3116. (PMID: 18776936)
Curr Opin Immunol. 2022 Aug;77:102209. (PMID: 35598506)
Sci Adv. 2019 Jan 02;5(1):eaav1882. (PMID: 30613781)
Viruses. 2021 May 04;13(5):. (PMID: 34064532)
J Biol Chem. 2015 Apr 17;290(16):10117-25. (PMID: 25737449)
Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6205-10. (PMID: 22492964)
J Virol. 2001 Oct;75(20):9986-90. (PMID: 11559832)
J Virol. 2020 Oct 27;94(22):. (PMID: 32878891)
J Mol Biol. 2013 Jun 12;425(11):1899-1914. (PMID: 23458406)
Proc Natl Acad Sci U S A. 2022 Mar 15;119(11):e2112008119. (PMID: 35263223)
Science. 2022 Oct 21;378(6617):263-269. (PMID: 36264808)
Proc Natl Acad Sci U S A. 2016 Nov 8;113(45):12768-12773. (PMID: 27791120)
Expert Rev Vaccines. 2017 Jan;16(1):55-63. (PMID: 27448771)
Mol Biol Evol. 2013 Apr;30(4):772-80. (PMID: 23329690)
JCI Insight. 2017 May 4;2(9):. (PMID: 28469084)
Lancet. 2002 Apr 27;359(9316):1478-83. (PMID: 11988247)
Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):6025-30. (PMID: 17392433)
J Virol. 2013 Jan;87(1):37-51. (PMID: 23097455)
PLoS Pathog. 2017 Dec 18;13(12):e1006735. (PMID: 29253863)
Hepatology. 2017 Apr;65(4):1117-1131. (PMID: 27997681)
Sci Adv. 2021 Mar 19;7(12):. (PMID: 33741598)
J Virol. 2002 Jul;76(14):6919-28. (PMID: 12072493)
Nature. 2005 Aug 18;436(7053):946-52. (PMID: 16107834)
Science. 2021 Feb 12;371(6530):735-741. (PMID: 33436524)
PLoS Pathog. 2019 May 17;15(5):e1007772. (PMID: 31100098)
Sci Rep. 2016 Jan 19;6:19234. (PMID: 26781591)
Nature. 2021 Oct;598(7881):521-525. (PMID: 34526719)
Sci Adv. 2020 Jul 24;6(30):eabb5642. (PMID: 32754640)
Clin Infect Dis. 2016 May 15;62(10):1287-1288. (PMID: 26936668)
Immunity. 1994 Dec;1(9):751-61. (PMID: 7895164)
Cold Spring Harb Perspect Med. 2021 Mar 1;11(3):. (PMID: 32341067)
Nature. 2014 Apr 17;508(7496):295-6. (PMID: 24740042)
PLoS Pathog. 2017 Feb 24;13(2):e1006235. (PMID: 28235087)
Science. 2016 Jul 22;353(6297):389-94. (PMID: 27463675)
EMBO J. 2002 Oct 1;21(19):5017-25. (PMID: 12356718)
Proc Natl Acad Sci U S A. 2018 Jan 2;115(1):E82-E91. (PMID: 29255018)
Sci Rep. 2015 Aug 04;5:12501. (PMID: 26238798)
J Virol. 2012 Dec;86(23):12582-90. (PMID: 22973048)
J Virol. 2017 Sep 27;91(20):. (PMID: 28794021)
Curr Opin Virol. 2016 Oct;20:55-63. (PMID: 27657659)
Comput Struct Biotechnol J. 2015 Nov 26;14:58-68. (PMID: 26862374)
PLoS One. 2013;8(3):e59776. (PMID: 23527266)
PLoS One. 2021 Mar 4;16(3):e0247963. (PMID: 33661993)
Curr Opin Virol. 2017 Apr;23:113-119. (PMID: 28550816)
Science. 2023 Jan 27;379(6630):eabn8934. (PMID: 36701450)
Cell Rep. 2022 May 24;39(8):110859. (PMID: 35613596)
J Virol. 2019 Jun 28;93(14):. (PMID: 31068427)
Nat Commun. 2023 Jan 26;14(1):433. (PMID: 36702826)
J Virol. 2005 Nov;79(21):13199-208. (PMID: 16227243)
J Virol. 2012 Dec;86(23):13085-8. (PMID: 22973046)
Gastroenterology. 2007 Feb;132(2):667-78. (PMID: 17258731)
Front Immunol. 2018 Jun 11;9:1315. (PMID: 29951061)
Influenza Other Respir Viruses. 2008 Nov;2(6):211-9. (PMID: 19453397)
N Engl J Med. 2014 Apr 24;370(17):1576-8. (PMID: 24720678)
J Infect Dis. 2011 Sep 1;204(5):811-3. (PMID: 21788452)
Nat Commun. 2021 May 11;12(1):2633. (PMID: 33976149)
Curr Opin Virol. 2021 Aug;49:92-101. (PMID: 34091143)
Am J Transplant. 2013 Apr;13(4):1047-1054. (PMID: 23356386)
Gastroenterology. 2010 Jan;138(1):315-24. (PMID: 19782080)
J Virol. 2008 Jan;82(2):966-73. (PMID: 17977972)
PLoS Pathog. 2015 Sep 30;11(9):e1005183. (PMID: 26421924)
Front Microbiol. 2018 Jan 15;8:2692. (PMID: 29379486)
Sci Transl Med. 2014 Sep 17;6(254):254ra129. (PMID: 25232181)
J Virol. 2008 Jun;82(12):6061-6. (PMID: 18400849)
Nucleic Acids Res. 2021 Jul 2;49(W1):W293-W296. (PMID: 33885785)
Sci Adv. 2020 Apr 15;6(16):eaaz6225. (PMID: 32494617)
Front Immunol. 2018 Sep 27;9:2146. (PMID: 30319614)
Viruses. 2021 May 05;13(5):. (PMID: 34063143)
Nat Med. 2008 Jan;14(1):25-7. (PMID: 18064037)
Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15394-9. (PMID: 8986822)
Gastroenterology. 2022 Feb;162(2):562-574. (PMID: 34655573)
Curr Opin Immunol. 2015 Aug;35:137-43. (PMID: 26241306)
Nat Commun. 2023 Jul 5;14(1):3980. (PMID: 37407593)
Proc Natl Acad Sci U S A. 2018 Jul 17;115(29):7569-7574. (PMID: 29954862)
Hepatology. 2014 Nov;60(5):1551-62. (PMID: 25043937)
Sci Transl Med. 2023 Apr 19;15(692):eade4790. (PMID: 37075129)
PLoS Comput Biol. 2020 Feb 28;16(2):e1007710. (PMID: 32109245)
PLoS Pathog. 2012;8(4):e1002653. (PMID: 22511875)
Nat Med. 2015 Sep;21(9):1065-70. (PMID: 26301691)
Nat Commun. 2022 Nov 25;13(1):7271. (PMID: 36434005)
Gut. 2021 Sep;70(9):1734-1745. (PMID: 33323394)
J Infect Dis. 2020 Mar 28;221(8):1304-1314. (PMID: 31074790)
Science. 2015 Aug 21;349(6250):790-1. (PMID: 26293940)
Gastroenterology. 2020 Mar;158(4):1058-1071.e6. (PMID: 31809725)
J Virol. 2013 Apr;87(8):4185-201. (PMID: 23365441)
Front Microbiol. 2014 Jul 03;5:329. (PMID: 25071742)
Gastroenterology. 2019 Jan;156(2):418-430. (PMID: 30268785)
Nature. 2014 May 15;509(7500):381-4. (PMID: 24553139)
Drug Deliv Transl Res. 2021 Aug;11(4):1401-1419. (PMID: 33694083)
Cell Host Microbe. 2018 Nov 14;24(5):703-716.e3. (PMID: 30439340)
NPJ Vaccines. 2024 Feb 21;9(1):39. (PMID: 38383616)
J Infect Dis. 2009 Oct 15;200(8):1216-26. (PMID: 19764883)
Cell Host Microbe. 2022 Dec 14;30(12):1732-1744.e7. (PMID: 36323313)
J Clin Invest. 2015 Jan;125(1):437-47. (PMID: 25500884)
J Mol Biol. 2001 Jan 12;305(2):259-67. (PMID: 11124904)
World J Gastroenterol. 2016 Sep 14;22(34):7824-40. (PMID: 27678366)
Front Immunol. 2018 Apr 27;9:910. (PMID: 29755477)
Nat Commun. 2019 May 29;10(1):2355. (PMID: 31142746)
Expert Rev Vaccines. 2016 Dec;15(12):1535-1544. (PMID: 27267297)
J Virol. 2014 Mar;88(5):2489-507. (PMID: 24352443)
Proc Natl Acad Sci U S A. 2016 Nov 8;113(45):E6946-E6954. (PMID: 27791171)
J Virol. 2015 Sep;89(17):9128-32. (PMID: 26085160)
J Virol. 2016 Jan 27;90(7):3745-59. (PMID: 26819303)
Antiviral Res. 2018 Dec;160:25-37. (PMID: 30217650)
Science. 2013 Nov 29;342(6162):1090-4. (PMID: 24288331)
J Pharm Sci. 2018 Sep;107(9):2283-2296. (PMID: 29763607)
J Clin Invest. 2019 Aug 13;129(11):4786-4796. (PMID: 31408439)
PLoS Pathog. 2012;8(8):e1002895. (PMID: 22952447)
Drug Discov Today. 2011 Jul;16(13-14):569-82. (PMID: 21570475)
Clin Infect Dis. 2013 Aug;57 Suppl 2:S46-50. (PMID: 23884065)
PLoS One. 2014 Jun 23;9(6):e100325. (PMID: 24956119)
ACS Nano. 2018 Sep 25;12(9):8855-8866. (PMID: 30028591)
BMC Biotechnol. 2014 Dec 24;14:111. (PMID: 25540031)
Front Immunol. 2014 Nov 10;5:550. (PMID: 25426115)
Hepatology. 2016 Dec;64(6):1922-1933. (PMID: 27641232)
Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10149-54. (PMID: 15220475)
Adv Mater. 2020 Apr;32(13):e1901255. (PMID: 31206841)
Sci Adv. 2020 Aug 26;6(35):eabb5938. (PMID: 32923643)
Proc Natl Acad Sci U S A. 2021 Jan 19;118(3):. (PMID: 33431677)
Science. 1998 Oct 30;282(5390):938-41. (PMID: 9794763)
Adv Sci (Weinh). 2023 Sep;10(27):e2301034. (PMID: 37526323)
Nature. 2011 Jun 08;474(7350):208-11. (PMID: 21654804)
Hepatology. 2014 Jun;59(6):2140-51. (PMID: 24425349)
J Virol. 2010 Nov;84(22):11905-15. (PMID: 20844034)
Virology. 1998 Sep 15;249(1):32-41. (PMID: 9740774)
J Virol. 2009 Dec;83(23):12473-82. (PMID: 19759151)
Vaccine. 2004 Jun 23;22(19):2396-405. (PMID: 15193401)
Virus Res. 2024 Mar;341:199308. (PMID: 38171391)
J Exp Med. 2016 Apr 4;213(4):469-81. (PMID: 27022144)
Front Immunol. 2018 May 31;9:1194. (PMID: 29904384)
NPJ Vaccines. 2023 Sep 25;8(1):138. (PMID: 37749081)
Lancet Infect Dis. 2012 May;12(5):408-14. (PMID: 22541630)
Curr Opin Virol. 2021 Oct;50:69-75. (PMID: 34403905)
Ther Adv Vaccines. 2014 Nov;2(6):159-82. (PMID: 25364509)
Nat Commun. 2021 Jan 14;12(1):372. (PMID: 33446655)
J Virol. 2000 Nov;74(22):10407-16. (PMID: 11044085)
N Engl J Med. 2011 Jun 23;364(25):2429-38. (PMID: 21696309)
J Virol. 2013 Feb;87(3):1605-17. (PMID: 23175356)
Science. 2013 Nov 1;342(6158):592-8. (PMID: 24179220)
Bioinformatics. 2005 Feb 1;21(3):379-84. (PMID: 15377502)

AI168048 United States NH NIH HHS; AI132213 United States NH NIH HHS; AI154100 United States NH NIH HHS

Keywords: HCV E1E2; nanoparticles; structure; vaccine

0 (Viral Envelope Proteins)
0 (Viral Hepatitis Vaccines)
157184-61-7 (glycoprotein E2, Hepatitis C virus)
0 (E1 protein, Hepatitis C virus)
0 (Antibodies, Neutralizing)
0 (Hepatitis C Antibodies)

Date Created: 20240525 Date Completed: 20240525 Latest Revision: 20240531

20240531

PMC11125608

10.3390/v16050803

38793684