High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection.
OBJECTIVE
Cellular immune responses are thought to play a key role in the resolution of primary HCV infection. Although it has been consistently shown that CD4+ T-cell responses are maintained in those with spontaneous resolution but lost in those with persistent infection, the role of CD8+ T-cell responses remains controversial. Previous studies have largely focused on limited HLA alleles and predefined CD8+ T-cell epitopes, and, thus, comprehensive studies remain to be performed.


METHODS
To understand the composition of the immune response associated with spontaneous resolution, we comprehensively mapped CD8+ T-cell responses in 20 HLA-diverse persons with resolved HCV infection, using HCV peptides spanning the entire genome. We analyzed the magnitude, breadth, function, and phenotype using ELISpot, class-I tetramers, intracellular cytokine staining, and cytolytic assays. We studied in parallel HCV-specific responses and viral sequence variation in persistent infection.


RESULTS
Responses in individuals with resolved infection were strong and broad with robust proliferation in response to antigen. Responses in those persistently infected were rarely detected ex vivo and, when present, were narrowly directed and weak. However, they also proliferated in vitro. Dominant target epitopes differed among individuals in both cohorts, despite frequently shared HLA-alleles.


CONCLUSIONS
These data indicate that persisting, strong CD8+ T-cell responses are observed in the majority of persons with resolved HCV infection and provide support for strategies to boost CD8+ T-cell responses for the prevention or treatment of HCV infection but also highlight the diversity of responses that may need to be elicited to provide protection.
Lauer
Georg M
GM
Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Barnes
Eleanor
E
Lucas
Michaela
M
Timm
Joerg
J
Ouchi
Kei
K
Kim
Arthur Y
AY
Day
Cheryl L
CL
Robbins
Gregory K
GK
Casson
Deborah R
DR
Reiser
Markus
M
Dusheiko
Geoffrey
G
Allen
Todd M
TM
Chung
Raymond T
RT
Walker
Bruce D
BD
Klenerman
Paul
P
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D012075:Remission, Spontaneous
D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens