Stable cytotoxic T cell escape mutation in hepatitis C virus is linked to maintenance of viral fitness.
Mechanisms by which hepatitis C virus (HCV) evades cellular immunity to establish persistence in chronically infected individuals are not clear. Mutations in human leukocyte antigen (HLA) class I-restricted epitopes targeted by CD8(+) T cells are associated with persistence, but the extent to which these mutations affect viral fitness is not fully understood. Previous work showed that the HCV quasispecies in a persistently infected chimpanzee accumulated multiple mutations in numerous class I epitopes over a period of 7 years. During the acute phase of infection, one representative epitope in the C-terminal region of the NS3/4A helicase, NS3(1629-1637), displayed multiple serial amino acid substitutions in major histocompatibility complex (MHC) anchor and T cell receptor (TCR) contact residues. Only one of these amino acid substitutions at position 9 (P9) of the epitope was stable in the quasispecies. We therefore assessed the effect of each mutation observed during in vivo infection on viral fitness and T cell responses using an HCV subgenomic replicon system and a recently developed in vitro infectious virus cell culture model. Mutation of a position 7 (P7) TCR-contact residue, I1635T, expectedly ablated the T cell response without affecting viral RNA replication or virion production. In contrast, two mutations at the P9 MHC-anchor residue abrogated antigen-specific T cell responses, but additionally decreased viral RNA replication and virion production. The first escape mutation, L1637P, detected in vivo only transiently at 3 mo after infection, decreased viral production, and reverted to the parental sequence in vitro. The second P9 variant, L1637S, which was stable in vivo through 7 years of follow-up, evaded the antigen-specific T cell response and did not revert in vitro despite being less optimal in virion production compared to the parental virus. These studies suggest that HCV escape mutants emerging early in infection are not necessarily stable, but are eventually replaced with variants that achieve a balance between immune evasion and fitness for replication.
Uebelhoer
Luke
L
Department of Medicine, Division of Infectious Diseases, Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Han
Jin-Hwan
JH
Callendret
Benoit
B
Mateu
Guaniri
G
Shoukry
Naglaa H
NH
Hanson
Holly L
HL
Rice
Charles M
CM
Walker
Christopher M
CM
Grakoui
Arash
A
D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007111:Immunity, Cellular; D009154:Mutation; D012641:Selection, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology*; D014779:Virus Replication
J Exp Med. 2005 Jun 6;201(11):1725-31
15939788
J Immunol. 2002 Sep 15;169(6):3447-58
12218168
J Exp Med. 2004 Nov 15;200(10):1243-56
15545352
Transplantation. 1996 Jul 27;62(2):147-54
8755808
Gastroenterology. 2001 Feb;120(2):512-24
11159892
N Engl J Med. 1992 Dec 31;327(27):1899-905
1280771
J Exp Med. 2004 Dec 20;200(12):1593-604
15611288
Virology. 1999 Sep 15;262(1):250-63
10489358
Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9294-9
15939869
Nat Med. 1999 Nov;5(11):1270-6
10545993
Immunol Lett. 2003 Jan 22;85(2):165-71
12527224
J Exp Med. 2005 Jun 6;201(11):1741-52
15939790
J Virol. 2003 Jun;77(12):6743-52
12767994
Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1294-8
7509068
J Virol. 2002 Dec;76(24):12423-34
12438568
World J Gastroenterol. 2007 Sep 28;13(36):4848-57
17828816
J Virol. 2007 Nov;81(22):12608-18
17728232
Science. 1999 Jul 2;285(5424):110-3
10390360
Nat Med. 2004 Mar;10(3):282-9
14770175
J Viral Hepat. 1999 Jan;6(1):35-47
10847128
Minerva Gastroenterol Dietol. 2004 Mar;50(1):21-8
15719003
Gastroenterology. 2003 Dec;125(6):1808-17
14724833
Science. 2005 Jul 22;309(5734):623-6
15947137
Immunity. 2001 Dec;15(6):883-95
11754811
CSH Protoc. 2006 Jul 01;2006(2):
22485828
J Clin Invest. 1997 Nov 1;100(9):2376-85
9410918
Nature. 1991 Dec 12;354(6353):453-9
1721107
Semin Liver Dis. 1995 Feb;15(1):41-63
7597443
Gastroenterology. 1998 Oct;115(4):954-65
9753499
J Virol. 2004 Mar;78(5):2581-5
14963161
J Virol. 2004 Dec;78(24):13901-10
15564498
J Exp Med. 2005 Jun 6;201(11):1753-9
15939791
Nat Med. 2004 Mar;10(3):275-81
14966520
Nat Med. 2005 Jul;11(7):791-6
15951748
J Exp Med. 2001 Nov 19;194(10):1395-406
11714747
Lancet. 1995 Oct 14;346(8981):1006-7
7475549
J Exp Med. 2003 May 19;197(10):1365-75
12743169
Nature. 2000 Sep 21;407(6802):386-90
11014195
Gut. 2006 Feb;55(2):266-74
16105887
Virology. 2008 Jul 5;376(2):397-407
18455749
J Exp Med. 2000 May 1;191(9):1499-512
10790425
Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15661-8
12441397
J Virol. 2006 Apr;80(7):3617-23
16537629
J Immunol. 1999 May 1;162(9):5584-91
10228041
Science. 2000 Dec 8;290(5498):1972-4
11110665
Eur J Immunol. 2005 Sep;35(9):2627-37
16114108
Science. 1998 Oct 2;282(5386):103-7
9756471
Immunity. 1999 Apr;10(4):439-49
10229187
Science. 2000 Apr 14;288(5464):339-44
10764648
J Clin Invest. 2004 Jul;114(2):250-9
15254592
Nat Med. 1997 Feb;3(2):205-11
9018240
N Engl J Med. 1999 Aug 19;341(8):556-62
10451460
Semin Liver Dis. 2000;20(1):1-16
10895428