31 August 2018 from 16:15 to 17:15

PhD defence Chris van Dorp

Rapidly evolving pathogens in a polymorphic host population: Modeling immuno-epidemiology of HIV-1 and influenza A virus

Pathogens adapt to their hosts on multiple levels. At the between-host level, natural selection acts on infectiousness and avoiding immunity. At the within-host level, pathogens are selected for immune escape and pathogen load. These selection pressures do not necessarily operate in concert, and this is further complicated by host-heterogeneity. In humans, the most striking example of heterogeneity is found in the human leukocyte antigens (HLA), which are cell-surface molecules used by the immune system to present epitopes to T cells.

This thesis regards the immunology and epidemiology of two viruses, influenza A virus (IAV) and HIV-1. In both cases, we study the escape from immune responses that are restricted to polymorphic HLA molecules, and the population-level consequences.

In the first part of the thesis, we relate antigenic drift of seasonal influenza with the sizes of annual epidemics. 
First, we investigate antigenic evolution of IAV. Most previous studies focused on the evolution of antibody antigens. Instead, we turn our attention to T-cell epitopes of IAV. These epitopes are used together with IAV protein sequences to construct an antigenic map of IAV, and we find evidence of a slow but steady decline in the number of epitopes over the past century. This decline suggests that IAV is adapting to human immune responses.

Next, we look for population-level effects of IAV adaptation.
Using data collected by Dutch general practitioners and a transmission model, we estimate the number of susceptible individuals at the start of 45 seasonal epidemics. The number of susceptible individuals is highly variable between years and age classes, but we find no evidence that this variation is due to the antigenic drift of the virus.

In the second part of the thesis, we develop two models of HIV-1 evolution. Population-level data suggests that HIV-1 has evolved its set-point virus load (SPVL) to maximize the population-level fitness. For example, the SPVL is partially inherited from transmitter to receiver, which is a necessary condition for fitness optimization. We aim to understand this maximization in the context of the polymorphic host population. First, we construct a relatively simple individual-based model of HIV-1 that uses a phenomenological description of the within-host evolution of the virus. This allows us to considerably simplify the representation of a virus. Our model does not predict maximization of the population-level fitness. Instead, the heritability of SPVL is largely explained by an immunological footprint of the hosts' immune responses.

As the first model is a bold simplification, we next present a more realistic HIV-1 model. The within-host model features coexisting HIV strains, and multiple immune responses, using the modeling framework of ordinary differential equations. Recent phylogenetic studies show that HIV-1 is becoming pre-adapted to hosts with certain HLA types. Although the model still does not predict maximization of the reproduction number, it can explain the emergence of heritability of the SPVL, and how associations emerge between HLA and viral polymorphisms.

Start date and time
31 August 2018 16:15
End date and time
31 August 2018 17:15
PhD candidate
C.H. van Dorp
Dissertation
Rapidly evolving pathogens in a polymorphic host population: Modeling immuno-epidemiology of HIV-1 and influenza A virus
PhD supervisor(s)
prof. dr. R.J. de Boer
Co-supervisor(s)
dr. M. van Boven