Spontaneous control of HCV is associated with expression of HLA-B 57 and preservation of targeted epitopes.
OBJECTIVE
HLA class I alleles are linked to spontaneous control of hepatitis C virus (HCV) and human immunodeficiency virus-1, but for HCV the roles of particular alleles and corresponding CD8(+) T-cell responses remain incompletely defined. We aimed to determine the correlations between these alleles and natural outcomes of HCV and determine associated key T-cell responses.


METHODS
In a cohort of HCV individuals, we determined HLA class I alleles, HCV outcomes, T-cell responses, and examined sequence data for mutational changes within key epitopes.


RESULTS
Carriage of HLA-B 57 was associated with a higher rate of viral clearance (risk ratio = 2.0; 95% confidence interval: 1.2-3.4), while HLA-B 08 was associated with a lower rate (risk ratio = 0.34; 95% confidence interval: 0.1-0.9]. Two HLA-B 57-restricted T-cell epitopes were targeted in spontaneous clearance; subjects with chronic viremia expressing HLA-B 57 harbored HCV strains with a high frequency of mutations in key residues. HLA-B 57-mediated escape was supported by diminished immune recognition of these variants and acute HCV infection revealing viral evolution toward less recognized variants. Analysis of a genotype 1b strain from a single-source HCV outbreak in which HLA-B 57 was not protective revealed sequence variations that interfere with immunogenicity, thereby preventing HLA-B 57-mediated immune pressure.


CONCLUSIONS
Our data indicate a role of HLA-B 57-restricted CD8(+) T-cell responses in mediating spontaneous clearance and evolution in HCV infection, and viral strains containing epitope variants that are less recognized abrogate the protective effects of HLA-B 57. The finding that HLA-B 57-mediated antiviral immunity is associated with control of both human immunodeficiency virus-1 and HCV suggests a common shared mechanism of a successful immune response against persistent viruses.
Kim
Arthur Y
AY
Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, GRB-504, Boston, Massachusetts 02114, USA. akim1@partners.org
Kuntzen
Thomas
T
Timm
Joerg
J
Nolan
Brian E
BE
Baca
Melanie A
MA
Reyor
Laura L
LL
Berical
Andrew C
AC
Feller
Andrea J
AJ
Johnson
Kristin L
KL
Schulze zur Wiesch
Julian
J
Robbins
Gregory K
GK
Chung
Raymond T
RT
Walker
Bruce D
BD
Carrington
Mary
M
Allen
Todd M
TM
Lauer
Georg M
GM
D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015331:Cohort Studies; D000939:Epitopes / Q000276:immunology; D005260:Female; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation
D000939:Epitopes; D015235:HLA-B Antigens; C103707:HLA-B57 antigen