HIV evolves very quickly permitting it to escape the immune system of an infected individual, limiting the effectiveness of drug treatment and making vaccine design extremely difficult. For these reasons identifying whether there are constraints on HIV evolution is of primary importance. In this thesis, I examined the relationships between sequence diversity and a number of factors including protein structure, co-evolution and RNA secondary structures, all of which contribute to evolutionary constraints. Firstly, I demonstrate that while there is an increase in sequence diversity over time, this variation has a tendency to be limited to specific structural regions. Relating the sequence variability of individual amino acid residues with three- dimensional protein structure, I find a significant difference between evolutionary rates in regions buried in the core of the protein as compared with those exposed on the surface. This result indicates that missense mutation is affected by structural constraints. Secondly, by relating recombinant breakpoint positions with the potential numbers of losses in amino acid interactions within the structure, I propose that as well as missense mutation, recombination is also affected by structural constraints, due to the need to maintain intra-molecular interactions. Thirdly, I demonstrate a relationship between conservation of RNA secondary structure and limited sequence variation in protein level, indicating RNA secondary structures are additional evolutionary constraint. This link between sequence and protein and RNA structures not only demonstrates the limits of recent HIV-1 evolution but also highlights the origins of evolutionary constraint on viral change. Lastly, I examined whether evolutionary constraints and co- evolution patterns of HIV genomes are applied in novel mosaic vaccine strategy and suggest that polyvalent mosaic vaccine sequence may generate proteins with stable structures and co-evolving units. Detailed understanding of the constraints that restrict HIV's possible evolution will inform analysis of drug and immune escape.
|Date of Award
|1 Aug 2013
- The University of Manchester
|David Robertson (Supervisor) & Simon Lovell (Supervisor)