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Gastroenterology. 2014 Oct;147(4):870-881.e8. doi: 10.1053/j.gastro.2014.07.005. Epub 2014 Jul 16.

Signatures of protective memory immune responses during hepatitis C virus reinfection.

Author information

1
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, Québec, Canada.
2
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
3
Institut National de Santé Publique du Québec, Laboratoire de Santé Publique du Québec (LSPQ), Sainte-Anne-de-Bellevue, Québec, Canada.
4
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de médecine familiale et de médecine d'urgence, Université de Montréal, Montréal, Québec, Canada.
5
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de médecine, Université de Montréal, Montréal, Québec, Canada. Electronic address: naglaa.shoukry@umontreal.ca.

Abstract

BACKGROUND & AIMS:

Development of a vaccine against hepatitis C virus (HCV) has been hindered by our limited understanding of immune correlates of protection during real-life exposure to the virus. We studied the immune response during HCV reinfection.

METHODS:

We analyzed blood samples from participants in the Montreal Acute Hepatitis C Injection Drug User Cohort Study who were reinfected with HCV from 2009 to 2012. Five patients spontaneously resolved their second infection and 4 developed chronic infections. We monitored the phenotypic and functional dynamics of HCV-specific memory T cell responses in all subjects during natural re-exposure and re-infection.

RESULTS:

Populations of CD4(+) and CD8(+) T cells with HCV-specific polyfunctional memory were expanded in all 5 individuals who resolved 2 successive HCV infections. We detected CD127(hi) HCV-specific memory CD8(+) T cells before reinfection regardless of a subject's ability to clear subsequent infections. Protection against viral persistence was associated with the expansion of a CD127(neg), PD1(lo) effector memory T cells at the peak of the response. We also observed broadening of T-cell response, indicating generation of de novo T-cell responses. The 4 individuals who failed to clear their subsequent infection had limited expansion of HCV-specific CD4(+) and CD8(+) memory T cells and expressed variable levels of the exhaustion marker PD1 on HCV-specific CD8(+) T cells. Dominant epitope regions of HCV strains isolated from patients with persistent reinfection had sequence variations that were not recognized by the pre-existing memory T cells.

CONCLUSIONS:

Protection from persistent HCV reinfection depends on the magnitude, breadth, and quality of the HCV-specific memory T-cell response. Sequence homology among viruses and ability of T cells to recognize multiple strains of HCV are critical determinants of protective memory.

KEYWORDS:

Cytokines; Immune Regulation; Protective Immunity; Viral Infection

PMID:
25038432
PMCID:
PMC4170061
DOI:
10.1053/j.gastro.2014.07.005
[Indexed for MEDLINE]
Free PMC Article

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