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Title: How does transmission in HIV influence the evolution of virulence?
Author: Shirreff, George
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Human Immunode ciency Virus (HIV) has a high mutation rate which allows it to evolve rapidly in response to selective pressures. We explore how transmission may naturally select HIV virulence. Set-point viral load (SPVL), the level of stable viraemia in early asymptomatic infection, is linked with the severity of infection, and is used as a proxy for virulence. The rst part investigates the virulence-transmission trade-o , which has been identi ed in several host-pathogen systems. Previous work hypothesised that this trade-o favours HIV-1 viruses of intermediate SPVL which are optimal for transmission. We analysed a deterministic model incorporating host and viral contributions to SPVL, transmission rates and duration of infection. We estimate key parameters governing SPVL evolution and examine the rate of evolution towards intermediate virulence. This model was extended to incorporate stochasticity to investigate how the founding virulence a ected the probability of emergence into a new population. Strains of intermediate virulence were found to be more likely to emerge. The second part explored heritability of virulence. Several recent studies have estimated heritability of SPVL, mostly by comparing between individuals identi ed as transmission pairs, but one used phylogenetic comparative analysis instead, which is applicable to more datasets. Many methods are available for this approach, and we evaluate these using simulated and previously analysed data, and develop new methods. None were able to identify heritability below a substantial threshold, which was higher than many of the results in previous studies. The two most successful methods were applied to a new dataset from the Netherlands, with an ambiguous result suggesting borderline detectable heritability. This work explores the estimation of heritability using phylogenies and provides some further evidence for genuine heritability of SPVL. The models provide strong support for a previous hypothesis and a framework for investigating how HIV virulence evolves in populations.
Supervisor: Hanage, William ; Fraser, Christophe Sponsor: Imperial College London
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
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