The effect of the HLA B27 allele on the immune response to acute HCV in HIV infected patients

Alotaibi, Sultan Merja T. (2016) The effect of the HLA B27 allele on the immune response to acute HCV in HIV infected patients. PhD thesis, University of Glasgow.

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Abstract

In mono-infected individuals, the HLA-B27 allele is strongly associated with spontaneous clearance of HCV in association with a strong CD8+ response targeted against a single epitope within the HCV RNA-dependent RNA polymerase (NS5B). We studied variation across the whole HCV genome and T cell responses over time in a rare cohort of HLA-B27+ patients with acute HCV and HIV co-infection, the majority of whom progressed to chronicity.
We used next generation sequencing to detect changes within and outwith the immuno-dominant HLA-B27 restricted HCV-specific CD8+ T cell epitope NS5B2841-2849 (ARMILMTHF) during evolving progression of early HCV infection. Within the Acute HCV UK cohort, 10 patients carried the HLA B27 allele. Of these, 3/8 patients (37.5%) with HIV infection and 2/2 (100%) without HIV spontaneously cleared HCV (p=0.44). Sequential samples from nine HLA-B27+ patients (2 with monoinfection and 7 with HIV co-infection) were available for analysis (four spontaneous clearers and five evolving progressors). Mutations identified using NGS were assessed using a replicon genotype 1a system to evaluate viral fitness. Multiple mutations within the HLA-B27 restricted NS5B2841-2849 epitope were associated with progression to chroncity whereas patients who cleared the HCV infection spontaneously had no or only one mutation at this site (p=0.03). A triple NS5B2841-2849 mutant observed during progression to chronicity was associated with restored replication when compared to wild-type virus while single or double mutants were significantly associated with impaired replication (p=0.0495).
T cell responses measured in these patients using ELISpot and flow cytometry. HLA-B27+ patients had significantly higher IFN-γ responses than patients who were HLA-B27- (p=0.0014). Those who progressed to chronicity had lower IFN-γ responses than those who cleared HCV (p=0.0011). Mono-infected patients had higher IFN-γ responses compared to co-infected patients (p=0.0015).
HIV co-infection is associated with a lower likelihood of spontaneous clearance of HCV in HLA B27+ patients and this is associated with impaired T cell function in this group.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: HCV.
Subjects: Q Science > QR Microbiology
R Medicine > RC Internal medicine
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Centre for Virus Research
Supervisor's Name: Thomson, Dr. Emma
Date of Award: 2016
Depositing User: Dr. Sultan Alotaibi
Unique ID: glathesis:2016-7709
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 17 Nov 2016 08:46
Last Modified: 29 Nov 2016 09:35
URI: http://theses.gla.ac.uk/id/eprint/7709

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