How does transmission in HIV influence the evolution of virulence?
File(s)
Author(s)
Shirreff, George
Type
Thesis
Abstract
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.
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.
Version
Open Access
Date Issued
2012-10
Date Awarded
2012-12
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Hanage, William
Fraser, Christophe
Sponsor
Imperial College London
Publisher Department
School of Public Health
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)