Projects

Host Interaction in Hepatitis C Infection

An examination into Hepatitis C virus and host interactions in diverse populations: implications in HCV infection and outcome, disease progression, response to drug therapy and vaccine design.

Goals:

The purpose of this study is to examine the effect of host (HLA and other immunogenetic markers such as the Killer Immunoglobulin-like Receptors (KIR)) and viral genetic diversity on Hepatitis C virus (HCV) infection and clinical outcomes in ethnically homogenous HCV-infected cohorts from diverse HLA and viral populations.

Progress:

1) HCV adaptation to HLA-restricted immune responses in chronically HCV infected patients

We are currently performing HLA typing and viral sequencing on pretreatment samples from approximately 100 chronically HCV-infected patients from cohorts in Western Australia (WA) and 120 co-infected patients from the Swiss HIV cohort. Patients from these cohorts have well-documented clinical outcomes and data including genotype, viral load and sALT. High-resolution typing of HLA Class I and II has been performed on the majority of patients from the WA cohorts. HCV sequencing of the NS3 and NS5 region of the HCV genome is in progress for most patient samples. Additional samples from chronically HCV-infected patients are being sought from other cohorts. We have used bioinformatic programs developed by the Perth group 1 to analyse the host and viral data from each individual. Preliminary results from this population-based approach reveals: i) the identification of conserved and polymorphic sites within the HCV gneome are likely to reflect structural or functional constraints; ii) significant associations of specific HLA alleles with HCV mutations within and flanking known T cell epitopes; and iii) a large number of putative HLA-restricted T cell epitope residues with many HLA alleles present within these patients.

2) Effect of HLA and KIR on HCV infection outcome

Patients that have resolved their HCV infection have been identified in the Swiss HIV cohort. KIR and HLA typing will be performed on these patients and on chronically HCV-infected patients to examine the influence of KIR genes and haplotypes on HCV infection outcome. In addition, the interaction of HLA and KIR on HCV infection outcome will be investigated. Additional samples from patients that are known to have resolved their HCV infection are being sought from other cohorts.

Moore, C. B., John, M., James, I., Christiansen, F.T., Witt, C. S., & Mallal, S. A. 2002, “Evidence of HIV-1 adaptation to HLA-restricted immune responses ata a population level”, Science, vol 296, 24 May, pp. 1439-1443.

Coordinator:

Dr. Silvana Gaudieri

gaudieri@cyllene.uwa.edu.au or Silvana.Gaudieri@health.wa.gov.au

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