PMID- 17559151
OWN - NLM
STAT- MEDLINE
DCOM- 20070830
LR  - 20161019
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 46
IP  - 2
DP  - 2007 Aug
TI  - Human leukocyte antigen-associated sequence polymorphisms in hepatitis C virus 
      reveal reproducible immune responses and constraints on viral evolution.
PG  - 339-49
AB  - 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.
FAU - Timm, Joerg
AU  - Timm J
AD  - Partners AIDS Research Center, Infectious Disease Division, Massachusetts General 
      Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Li, Bin
AU  - Li B
FAU - Daniels, Marcus G
AU  - Daniels MG
FAU - Bhattacharya, Tanmoy
AU  - Bhattacharya T
FAU - Reyor, Laura L
AU  - Reyor LL
FAU - Allgaier, Rachel
AU  - Allgaier R
FAU - Kuntzen, Thomas
AU  - Kuntzen T
FAU - Fischer, Will
AU  - Fischer W
FAU - Nolan, Brian E
AU  - Nolan BE
FAU - Duncan, Jared
AU  - Duncan J
FAU - Schulze zur Wiesch, Julian
AU  - Schulze zur Wiesch J
FAU - Kim, Arthur Y
AU  - Kim AY
FAU - Frahm, Nicole
AU  - Frahm N
FAU - Brander, Christian
AU  - Brander C
FAU - Chung, Raymond T
AU  - Chung RT
FAU - Lauer, Georg M
AU  - Lauer GM
FAU - Korber, Bette T
AU  - Korber BT
FAU - Allen, Todd M
AU  - Allen TM
LA  - eng
GR  - P01 AI061734/AI/NIAID NIH HHS/United States
GR  - AI067926/AI/NIAID NIH HHS/United States
GR  - R01 AI067926/AI/NIAID NIH HHS/United States
GR  - P01 AI061734-02/AI/NIAID NIH HHS/United States
GR  - AI066345/AI/NIAID NIH HHS/United States
GR  - U19 AI066345/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Viral Nonstructural Proteins)
SB  - IM
MH  - Amino Acid Sequence
MH  - CD4 Lymphocyte Count
MH  - CD8-Positive T-Lymphocytes/*immunology
MH  - Epitopes, T-Lymphocyte
MH  - Genes, MHC Class I
MH  - Hepacivirus/genetics/*immunology
MH  - Hepatitis C/*immunology
MH  - Histocompatibility Antigens Class I/*immunology
MH  - Humans
MH  - Phylogeny
MH  - Sequence Alignment
MH  - Viral Nonstructural Proteins/*chemistry
EDAT- 2007/06/15 09:00
MHDA- 2007/08/31 09:00
CRDT- 2007/06/15 09:00
PHST- 2007/06/15 09:00 [pubmed]
PHST- 2007/08/31 09:00 [medline]
PHST- 2007/06/15 09:00 [entrez]
AID - 10.1002/hep.21702 [doi]
PST - ppublish
SO  - Hepatology. 2007 Aug;46(2):339-49. doi: 10.1002/hep.21702.