title: Integrating genealogical and dynamical modelling to infer escape and reversion rates in HIV epitopes.
abstract: The rates of escape and reversion in response to selection pressure arising from the host immune system, notably the cytotoxic T-lymphocyte (CTL) response, are key factors determining the evolution of HIV. Existing methods for estimating these parameters from cross-sectional population data using ordinary differential equations (ODEs) ignore information about the genealogy of sampled HIV sequences, which has the potential to cause systematic bias and overestimate certainty. Here, we describe an integrated approach, validated through extensive simulations, which combines genealogical inference and epidemiological modelling, to estimate rates of CTL escape and reversion in HIV epitopes. We show that there is substantial uncertainty about rates of viral escape and reversion from cross-sectional data, which arises from the inherent stochasticity in the evolutionary process. By application to empirical data, we find that point estimates of rates from a previously published ODE model and the integrated approach presented here are often similar, but can also differ several-fold depending on the structure of the genealogy. The model-based approach we apply provides a framework for the statistical analysis and hypothesis testing of escape and reversion in population data and highlights the need for longitudinal and denser cross-sectional sampling to enable accurate estimate of these key parameters.
authors.affiliation: Department of Statistics, 1 South Parks Road, University of Oxford, Oxford OX1 3TG, UK. duncan.palmer@stats.ox.ac.uk
authors.forename: Duncan
authors.initials: D
authors.lastname: Palmer
authors.forename: John
authors.initials: J
authors.lastname: Frater
authors.forename: Rodney
authors.initials: R
authors.lastname: Phillips
authors.forename: Angela R
authors.initials: AR
authors.lastname: McLean
authors.forename: Gil
authors.initials: G
authors.lastname: McVean
mesh_terms: D000956:Antigens, Viral / Q000276:immunology*; D003198:Computer Simulation; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D019143:Evolution, Molecular; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D010802:Phylogeny; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; D054302:pol Gene Products, Human Immunodeficiency Virus
keywords: HIV; cytotoxic T-lymphocyte; escape; genealogy; peeling; phylodynamics