Viral fitness, genomic recombination, and immune evasion: Mechanisms of HIV evolution across scales

Thesis

The within-host evolution of HIV is characterised by rapid selection of immune-evasion mutations, pervasive recombination, and vast fitness landscapes, making it one of the fastest evolving organisms. The enormous evolutionary capacity of the virus has challenged therapeutic development, with a cure remaining elusive and drug resistance continues to be a concern. In contrast, between-host evolution shows evidence of neutral evolution, with multiple subtypes coexisting globally. Selection pressures and fitness trade-offs can vary or conflict across within and between-host scales, and the impact of within-host selection on the virus circulating at a population level is not fully understood. In this thesis, I investigate the evolutionary forces driving viral dynamics, focusing on how selection and recombination shape viral populations within and between hosts. Using whole-genome deep sequencing data from hundreds of longitudinally sampled transmission pairs in sub-Saharan Africa, I explore several aspects of viral evolution.

First, I examine virulence evolution as a classic example of the conflict between withinhost and between-host selection. Through modelling viral load as determined by the number of weakly deleterious mutations across many segregating sites, I demonstrate how between-host selection for transmission fitness can overcome short-term evolutionary pressures within-host as a result of the balance between mutation and selection pressure. I then investigate recombination, a major source of viral genetic diversity, discussing challenges in accurately inferring recombination rates in dynamic, rapidly evolving viral populations. I identify consistent recombination hot and cold spots across the genome that persist across subtypes and sequencing platforms, corresponding with previously identified inter-subtype patterns. I then quantify the evolutionary rate at both the within and between-host scales across the genome, proposing that transient, high-frequency mutations (“toggling” mutations) explain discrepancies in rate estimation across the two scales. Finally, I show that CTL escape mutations dominate early viral evolution and undergo selection and reversion during transmission, linking these dynamics to within-host toggling at the amino acid level.

This work reveals general principles of viral evolution that persist across hosts, subtypes, and scales. The findings have important implications for understanding the long-term impact of immune pressures, the balance of selection forces, and methodological approaches to studying rapidly evolving viruses.

Authors: Longley, H

• DOI: 10.5287/ora-7rowdgnvg
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English