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


CONCLUSIONS
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.
Timm
Joerg
J
Partners AIDS Research Center, Infectious Disease Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Li
Bin
B
Daniels
Marcus G
MG
Bhattacharya
Tanmoy
T
Reyor
Laura L
LL
Allgaier
Rachel
R
Kuntzen
Thomas
T
Fischer
Will
W
Nolan
Brian E
BE
Duncan
Jared
J
Schulze zur Wiesch
Julian
J
Kim
Arthur Y
AY
Frahm
Nicole
N
Brander
Christian
C
Chung
Raymond T
RT
Lauer
Georg M
GM
Korber
Bette T
BT
Allen
Todd M
TM
D000595:Amino Acid Sequence; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte; D005805:Genes, MHC Class I; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D010802:Phylogeny; D016415:Sequence Alignment; D017361:Viral Nonstructural Proteins / Q000737:chemistry*
D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D017361:Viral Nonstructural Proteins