Mathematical Modeling of the Within-host Dynamics and Evolution of the Human Immunodeficiency Virus.
Abstract: The human immunodeficiency virus (HIV) is one of the fastest
evolving entities known. Solving the public health problems it poses necessitates a
detailed understanding of the evolutionary processes underlying its spread and persistence.
Many of the parameters that govern the course of infection in an individual are not
directly measurable in the lab. Mathematical and computational mo... read moredeling has been successful
in estimating many of these parameters by building models that can reproduce the dynamics
of various cell types that are observed. Accurate models can be used to aid in the
interpretation of data and predict the effect of therapeutic interventions. This thesis
focuses on building realistic models of the interaction of HIV with the host immune system.
First, we describe HIV adaptation to a host in a chronic infection. The system is simulated
by means of a novel Monte-Carlo algorithm including the evolutionary factors of mutation,
positive selection with varying strength among sites, random genetic drift, linkage and
recombination. By comparing several observables measured in simulation to the same
quantities calculated in patient data, we estimate the effective recombination rate and the
average selection coefficient to be on the order of 1% per genome per generation and 0.5%,
respectively. Next, we simulate virus evolution under dynamical selection pressure from
multiple Cytotoxic T Lymphocytes (CTL) in order to quantify the impact of changing CTL
levels on the pattern of emergence of immune escapes in CTL epitopes. We conclude that
changing CTL levels can give rise to complex, non-nested patterns of intra-epitope
variation. Finally, we proposed a model to explain the outcome of vaccination in animals
challenged with two viruses, SIVmac251 and SHIV. To explain the mechanism behind the effect
of vaccination, we propose a model including two types of CTL regulation, the helper
cell-dependent and helper cell-independent response, which control infection in vaccinated
and unvaccinated animals, respectively.
Thesis (Ph.D.)--Tufts University, 2012.
Submitted to the Dept. of Physics.
Advisors: Igor Rouzine, and Leon Gunther.
Committee: Peggy Cebe, and Krzysztof Sliwa.
Keywords: Biophysics, and Virology.read less