Project plan, M.Sc. Thesis in Bioinformatics

Estimating minimum host population size for Varicella zoster virus given different assumptions of reinfections

Supervisors

Peter Norberg, PhD

0735-316166
Dept. of Infectious Medicine,
Sahlgrenska Academy
University of Gothenburg / Devdatt Dubhashi, Prof.
Dept. of Computer Science
Chalmers University of Technology

Background

Herpesviruses are ubiquitous pathogens infecting a wide range of animals, including humans. Nine herpesviruses infect humans, of which herpes simplex Virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella zoster virus (VZV) belongs to the alphaherpesvirinaesubfamily. VZV causes chickenpox at primary infection and establish lifelong latency in sensory and trigeminal ganglia. Later in life, the virus may reactivate to cause herpes zoster.

All herpesviruses have been thought to evolve with a relatively constant evolutionary clock. Phylogenetic studies have demonstrated that clinical HSV-1 strains can be divided into at least three evolutionary clades [1], and that VZV can be divided into at least six evolutionary clades [2-4]. However, recent phylogenetic studies suggest that the evolutionary clock may differ drastically between VZV and HSV-1. Although these two viruses are highly similar genetically and phenotypically with similar genetic machineries for replication and miss-match repair, the internal branch lengths are significantly longer for HSV-1 than for VZV. We have suggested that the underlying reasons explaining these differences does not depend on differences in times since the most recent common ancestor, nor in proof-reading capacity[5]. Instead, these differences likely depend on different numbers of replication cycles per year for HSV-1 and VZV. We believe that the VZV infection always can be described in cycles. That is, primary infection (chicken pox) –> latency for many year (~60 years) -> reactivation (Zoster), which triggers a new chicken pox outbreak (primary infection) -> latency ->…. The different branch lengths would thus be explained by different durations of latency periods for HSV-1 and VZV, and frequencies of reactivation. The general apprehension has been that the virus is continuously spreading chicken pox -> chicken pox, with only sporadic activations from zoster. However, we believe that the size of the host populations (humans) is, and more importantly, has been, far too small to sustain continuously spreading chicken pox outbreaks other than for very short periods, infecting relatively few persons. Instead, we believe that latency followed by reactivation (when new susceptible hosts have been born) is essential for the survival of VZV.

Purpose

The main purpose of this project is to create anepidemiological model that can be used to estimate the minimum host population size needed for VZV to survive, with and without reactivation (Zoster). The minimum host population size can be used to determine if the reactivation (Zoster) has been necessary for the virus to survive. It may also have relevance for predictions of future evolution of VZV, particularly in large cities.

Methodology

This project will look at existing epidemiological models, and adapt/improve them in order to implement a new model for Varicella that can also model reinfections from Zoster. The new model will be used to investigate which host population sizes that are required to sustain the disease, with and without reactivation.

References

1.Norberg, P., et al., Phylogenetic analysis of clinical herpes simplex virus type 1 isolates identified three genetic groups and recombinant viruses. J Virol, 2004. 78(19): p. 10755-64.

2.Norberg, P., et al., Complete-genome phylogenetic approach to varicella-zoster virus evolution: genetic divergence and evidence for recombination. J Virol, 2006. 80(19): p. 9569-76.

3.Peters, G.A., et al., A full-genome phylogenetic analysis of varicella-zoster virus reveals a novel origin of replication-based genotyping scheme and evidence of recombination between major circulating clades. J Virol, 2006. 80(19): p. 9850-60.

4.Norberg, P., et al., Recombination of Globally Circulating Varicella Zoster Virus. J Virol, 2015.

5.Norberg, P., et al., A genome-wide comparative evolutionary analysis of herpes simplex virus type 1 and varicella zoster virus. PLoS One, 2011. 6(7): p. e22527.