The impact of immunosuppression on nucleotide sequence diversity in the first hypervariable region (HVR1) of hepatitis C virus (HCV).

Lawal, Zarah Yetunde (1997). The impact of immunosuppression on nucleotide sequence diversity in the first hypervariable region (HVR1) of hepatitis C virus (HCV). PhD thesis The Open University.



Hepatitis C virus (HCV) is responsible for most cases of non-A, non-B hepatitis. The persistent nature of this virus has been attributed to viral replication errors, which lead to a dynamic pool of antigenic variants that allow escape from the host immune response. A major part of this escape is due to the hypervariable region 1 (HVR1) of HCV, known to encode structurally flexible, isolate-specific neutralising epitopes which undergo successive genetic alterations. In a substantial number of cases, complications of HCV infection lead to end-stage liver disease for which the only treatment is orthotopic liver transplantation (OLT). Primary HCV infection of the allograft is an almost universal phenomenon associated with OLT. This study focused on the pattern of HCV variability in the context of immunosuppression, which is a feature of post-OLT treatment. Sequences of the HCV HVR1 derived from OLT recipients and from asymptomatic (presumably immunocompetent) carriers of the virus were compared over several time-points. A rapid turnover of sequences was found in the untreated subjects, in whom mean nucleotide and amino acid sequence diversity were 19.8% and 43.5%, respectively. In the immunosuppressed patients, the corresponding figures were 2.3% and 2.3%. Untreated subjects showed a ratio of transitional to transversional mutations of 2.57, compared with 0.98 for untreated subjects (p = 0.0165). Similarly, the replacement to silent mutation (R/S) ratios were 8.22 and 1.33 (p = 0.0069), respectively. The major differences between the two groups of patients were especially demonstrated by a subset of two immunosuppressed patients, in whom the HVRl showed almost 100% homogeneity throughout a year of follow-up. Both patients required re-transplantation within a year of the first OLT, and both died of HCV-related disease shortly afterwards. On the other hand, two other transplant recipients, who showed an HVRl mutation rate indistinguishable from that found in the untreated group, remain well 10 months and almost two years post-OLT. This investigation (1) demonstrated that the HCV genome becomes more homogenous post-OLT; (2) suggests that, at least in some patients, the lack of genetic heterogeneity may pre-date liver transplantation; (3) highlights the critical nature of host factors in determining the clinical course of post-OLT recurrent HCV infection; and (4) provides a model of hepatitis C viral kinetics in immunosuppressed and untreated individuals. The finding of HCV genomic sequences within the leukocytes provides molecular evidence for the existence of HCV in peripheral blood cells, and thus supports the hypothesis that peripheral blood lymphocytes act as HCV reservoirs for the reinfecting virions.

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