Viral sequence evolution in acute hepatitis C virus infection.
CD8(+)-T-cell responses play an important role in the containment and clearance of hepatitis C virus (HCV) infection, and an association between viral persistence and development of viral escape mutations has been postulated. While escape from CD8+ -T-cell responses has been identified as a major driving force for the evolution of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), a broader characterization of this relationship is needed in HCV infection. To determine the extent, kinetics, and driving forces of HCV sequence evolution, we sequenced the entire HCV genome longitudinally in four subjects monitored for up to 30 months after acute infection. For two subjects the transmission sources were also available. Of 53 total non-envelope amino acid substitutions detected, a majority represented forward mutations away from the consensus sequence. In contrast to studies in HIV and SIV, however, only 11% of these were associated with detectable CD8+ T-cell responses. Interestingly, 19% of non-envelope mutations represented changes toward the consensus sequence, suggesting reversion in the absence of immune pressure upon transmission. Notably, the rate of evolution of forward and reverse mutations correlated with the conservation of each residue, which is indicative of structural constraints influencing the kinetics of viral evolution. Finally, the rate of sequence evolution was observed to decline over the course of infection, possibly reflective of diminishing selection pressure by dysfunctional CD8+ T cells. Taken together, these data provide insight into the extent to which HCV is capable of evading early CD8+ T-cell responses and support the hypothesis that dysfunction of CD8+ T cells may be associated with failure to resolve HCV infections.
Kuntzen
Thomas
T
Massachusetts General Hospital, Infectious Disease, 13th Street, Charlestown, MA 02129, USA.
Timm
Joerg
J
Berical
Andrew
A
Lewis-Ximenez
Lia L
LL
Jones
Andrea
A
Nolan
Brian
B
Schulze zur Wiesch
Julian
J
Li
Bin
B
Schneidewind
Arne
A
Kim
Arthur Y
AY
Chung
Raymond T
RT
Lauer
Georg M
GM
Allen
Todd M
TM
D000596:Amino Acids / Q000737:chemistry; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry; D019143:Evolution, Molecular; D016679:Genome, Viral; D006680:HLA Antigens / Q000737:chemistry; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000235:genetics / Q000821:virology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D013601:T-Lymphocytes / Q000378:metabolism
D000596:Amino Acids; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D007371:Interferon-gamma
J Exp Med. 2004 Dec 20;200(12):1593-604
15611288
Gastroenterology. 1999 Oct;117(4):933-41
10500077
J Virol. 2005 May;79(9):5721-31
15827187
J Exp Med. 2005 Jun 6;201(11):1725-31
15939788
J Exp Med. 2005 Jun 6;201(11):1741-52
15939790
J Exp Med. 2005 Jun 6;201(11):1753-9
15939791
Hepatology. 2005 Jul;42(1):104-12
15962289
J Virol. 2004 Dec;78(24):14012-22
15564508
Clin Infect Dis. 2005 Sep 1;41(5):667-75
16080089
J Virol. 2005 Nov;79(21):13239-49
16227247
J Immunol. 2005 Dec 1;175(11):7519-29
16301660
J Virol. 2005 Dec;79(24):15131-41
16306585
Gut. 2006 Feb;55(2):266-74
16105887
J Virol. 2006 Feb;80(4):1637-44
16439520
J Virol. 2006 Apr;80(7):3617-23
16537629
Clin Infect Dis. 2006 May 1;42(9):1254-9
16586384
J Virol. 2006 Nov;80(22):11094-104
17071929
J Virol. 2007 Jan;81(1):193-201
17065207
Gastroenterology. 2007 Feb;132(2):667-78
17258731
Science. 2007 Mar 16;315(5818):1583-6
17363674
J Infect Dis. 2000 May;181(5):1528-36
10823750
Nature. 2000 Sep 21;407(6802):386-90
11014195
Nat Med. 2000 Dec;6(12):1348-54
11100119
J Virol. 2001 Feb;75(3):1229-35
11152496
Gastroenterology. 2001 Feb;120(2):512-24
11159892
J Exp Med. 2001 Nov 19;194(10):1395-406
11714747
Immunity. 2001 Dec;15(6):883-95
11754811
Nature. 2002 Jan 17;415(6869):335-9
11797012
J Virol. 2002 Mar;76(6):2817-26
11861849
Clin Exp Immunol. 2002 May;128(2):195-203
11985510
J Virol. 2002 Jun;76(12):6104-13
12021343
Science. 2002 May 24;296(5572):1439-43
12029127
J Immunol. 2002 Sep 15;169(6):3447-58
12218168
Hepatology. 2002 Nov;36(5 Suppl 1):S1-2
12407571
J Virol. 2004 Mar;78(5):2581-5
14963161
Nat Med. 2004 Mar;10(3):282-9
14770175
Nat Med. 2004 Mar;10(3):275-81
14966520
J Virol. 2004 Jul;78(13):7069-78
15194783
J Virol. 2004 Sep;78(18):9782-9
15331711
Gastroenterology. 2004 Sep;127(3):924-36
15362047
J Gen Virol. 2004 Nov;85(Pt 11):3173-88
15483230
Hepatology. 2004 Nov;40(5):1062-71
15486925
Biometrics. 1988 Dec;44(4):1049-60
3233245
N Engl J Med. 1991 Jul 11;325(2):98-104
1646962
Semin Liver Dis. 1995 Feb;15(1):41-63
7597443
Nat Med. 1997 Feb;3(2):212-7
9018241
J Clin Invest. 1997 Nov 1;100(9):2376-85
9410918
J Virol. 1998 Jan;72(1):886-7
9420306
Hepatology. 1998 Jan;27(1):223-7
9425941
Immunity. 1999 Apr;10(4):439-49
10229187
Clin Infect Dis. 2005 Apr 1;40(7):951-8
15824985