Human leukocyte antigen-associated sequence polymorphisms in hepatitis C virus reveal reproducible immune responses and constraints on viral evolution
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Human leukocyte antigen-associated sequence polymorphisms in hepatitis C virus reveal reproducible immune responses and constraints on viral evolution. / Timm, Joerg; Li, Bin; Daniels, Marcus G; Bhattacharya, Tanmoy; Reyor, Laura L; Allgaier, Rachel; Kuntzen, Thomas; Fischer, Will; Nolan, Brian E; Duncan, Jared; Schulze zur Wiesch, Julian; Kim, Arthur Y; Frahm, Nicole; Brander, Christian; Chung, Raymond T; Lauer, Georg M; Korber, Bette T; Allen, Todd M.
in: HEPATOLOGY, Jahrgang 46, Nr. 2, 08.2007, S. 339-49.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -