Human leukocyte antigen-associated sequence polymorphisms in hepatitis C virus reveal reproducible immune responses and constraints on viral evolution

TY - JOUR

T1 - Human leukocyte antigen-associated sequence polymorphisms in hepatitis C virus reveal reproducible immune responses and constraints on viral evolution

AU - Timm, Joerg

AU - Li, Bin

AU - Daniels, Marcus G

AU - Bhattacharya, Tanmoy

AU - Reyor, Laura L

AU - Allgaier, Rachel

AU - Kuntzen, Thomas

AU - Fischer, Will

AU - Nolan, Brian E

AU - Duncan, Jared

AU - Schulze zur Wiesch, Julian

AU - Kim, Arthur Y

AU - Frahm, Nicole

AU - Brander, Christian

AU - Chung, Raymond T

AU - Lauer, Georg M

AU - Korber, Bette T

AU - Allen, Todd M

PY - 2007/8

Y1 - 2007/8

N2 - UNLABELLED: CD8(+) T cell responses play a key role in governing the outcome of hepatitis C virus (HCV) infection, and viral evolution enabling escape from these responses may contribute to the inability to resolve infection. To more comprehensively examine the extent of CD8 escape and adaptation of HCV to human leukocyte antigen (HLA) class I restricted immune pressures on a population level, we sequenced all non-structural proteins in a cohort of 70 chronic HCV genotype 1a-infected subjects (28 subjects with HCV monoinfection and 42 with HCV/human immunodeficiency virus [HIV] coinfection). Linking of sequence polymorphisms with HLA allele expression revealed numerous HLA-associated polymorphisms across the HCV proteome. Multiple associations resided within relatively conserved regions, highlighting attractive targets for vaccination. Additional mutations provided evidence of HLA-driven fixation of sequence polymorphisms, suggesting potential loss of some CD8 targets from the population. In a subgroup analysis of mono- and co-infected subjects some associations lost significance partly due to reduced power of the utilized statistics. A phylogenetic analysis of the data revealed the substantial influence of founder effects upon viral evolution and HLA associations, cautioning against simple statistical approaches to examine the influence of host genetics upon sequence evolution of highly variable pathogens.CONCLUSION: These data provide insight into the frequency and reproducibility of viral escape from CD8(+) T cell responses in human HCV infection, and clarify the combined influence of multiple forces shaping the sequence diversity of HCV and other highly variable pathogens.

AB - UNLABELLED: CD8(+) T cell responses play a key role in governing the outcome of hepatitis C virus (HCV) infection, and viral evolution enabling escape from these responses may contribute to the inability to resolve infection. To more comprehensively examine the extent of CD8 escape and adaptation of HCV to human leukocyte antigen (HLA) class I restricted immune pressures on a population level, we sequenced all non-structural proteins in a cohort of 70 chronic HCV genotype 1a-infected subjects (28 subjects with HCV monoinfection and 42 with HCV/human immunodeficiency virus [HIV] coinfection). Linking of sequence polymorphisms with HLA allele expression revealed numerous HLA-associated polymorphisms across the HCV proteome. Multiple associations resided within relatively conserved regions, highlighting attractive targets for vaccination. Additional mutations provided evidence of HLA-driven fixation of sequence polymorphisms, suggesting potential loss of some CD8 targets from the population. In a subgroup analysis of mono- and co-infected subjects some associations lost significance partly due to reduced power of the utilized statistics. A phylogenetic analysis of the data revealed the substantial influence of founder effects upon viral evolution and HLA associations, cautioning against simple statistical approaches to examine the influence of host genetics upon sequence evolution of highly variable pathogens.CONCLUSION: These data provide insight into the frequency and reproducibility of viral escape from CD8(+) T cell responses in human HCV infection, and clarify the combined influence of multiple forces shaping the sequence diversity of HCV and other highly variable pathogens.

KW - Amino Acid Sequence

KW - CD4 Lymphocyte Count

KW - CD8-Positive T-Lymphocytes/immunology

KW - Epitopes, T-Lymphocyte

KW - Genes, MHC Class I

KW - Hepacivirus/genetics

KW - Hepatitis C/immunology

KW - Histocompatibility Antigens Class I/immunology

KW - Humans

KW - Phylogeny

KW - Sequence Alignment

KW - Viral Nonstructural Proteins/chemistry

U2 - 10.1002/hep.21702

DO - 10.1002/hep.21702

M3 - SCORING: Journal article

C2 - 17559151

VL - 46

SP - 339

EP - 349

JO - HEPATOLOGY

JF - HEPATOLOGY

SN - 0270-9139

IS - 2

ER -