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Evolution and kinetics of hepatitis B virus during primary infection in humans: Relevance to virulence and outcome

Whalley, Simon Adam; (2003) Evolution and kinetics of hepatitis B virus during primary infection in humans: Relevance to virulence and outcome. Doctoral thesis (M.D), UCL (University College London). Green open access

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Abstract

From a single source outbreak of hepatitis B virus (HBV) infection, we characterized the kinetics and evolution of primary HBV infection incorporating incubation and clinical phases of disease, in six patients with acute resolving hepatitis and four patients who progressed to chronic infection. We estimate a basic reproductive number of 5.5 and a peak HBV production rate of at least 10^13 virions/day. HBV replicates rapidly with mean doubling time of 3.7 ± 1.5 days. After a peak viral load in serum of nearly 10^10 HBV DNA copies/ml, clearance of HBV DNA follows a two or three phase decay pattern with an initial rapid decline characterized by mean half-life (t1/2) of 3.7 ± 1.2 days, similar to the t1/2 observed in the non-cytolytic clearance of cccDNA for other hepadnaviruses. The final phase of virion clearance occurs at a variable rate (t1/2 of 4.8 to 284 days) and may relate to the rate of loss of infected hepatocytes. Using denaturing gradient gel electrophoresis to screen PCR-clones for mutations in two genetic loci (3 ORF: core, surface, and polymerase) we found 95 mutations in over 1.2 Mbp of genetic sequence analysed, indicating a relatively stable genetic population. Patients with acute resolving hepatitis B exhibited a higher genetic diversity in both loci compared to chronic infection. All non-synonymous mutations in the core occurred in regions mapped as B (including anti-HBe), CD4+ or CD8+ epitopes. Non-synonymous mutations also occurred in the highly conserved region of the polymerase gene, and in CTL epitopes and B cell a determinant of HBsAg. Extensive deletions encompassing these epitopes occurred in all ORF's. Mutation in CD8+ 18-27 epitope of HLA A*0201 patients significantly correlated with CTL CD8+ response to this epitope and resolution of acute infection. Thus, the broadly reactive nature of the immune response was capable of clearing such evolving mutants and preventing viral persistence, though perhaps at the expense of acute hepatocellular injury.

Type: Thesis (Doctoral)
Qualification: M.D
Title: Evolution and kinetics of hepatitis B virus during primary infection in humans: Relevance to virulence and outcome
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Hepatitis B
URI: https://discovery.ucl.ac.uk/id/eprint/10119883
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