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Abstract
Human immunodeficiency virus (HIV) continues to be a major global health problem. Decades of research have still not produced a successful vaccine and understanding many aspects of this virus and HIV infection continues to challenge researchers. In this thesis I have addressed several key questions about HIV biology and infection using a computational biology approach.
Macaque models of HIV infection play an important role in HIV research and yet the viral peptides presented by MHC Class-I and recognised by cytotoxic T-lymphocytes (CTL) in macaques are not well characterised. I developed an in-house bioinformatics pipeline to investigate novel CTL epitopes and their associated patterns of escape mutations in pigtailed macaques. I identified new potential CTL epitopes and numerous novel non-synonymous point mutations and regions of non-synonymous mutation associated with specific MHC-I haplotypes.
I also investigated the nature and distribution of APOBEC3-induced hypermutation signatures and whether this information provides clues about the HIV inhibition by different APOBEC3 enzymes such as APOBEC3G and APOPEC3F. I developed a new method for hypermutation detection. I also used a novel approach to identify preferential patterns of G-to-A mutation for both APOBEC3G and APOBEC3F.
The source of CpG depletion in the HIV genome is another aspect of HIV biology that is not well understood. My bioinformatics analyses suggest that the methylation mechanism may be responsible for depletion of CpG dinucleotides in the HIV genome. Importantly, the results showed that viral genome adaptation to the host CpG machinery is a highly specific pattern that is only observed in HIV and its simian counterpart, SIV.
The thesis finally reports a meta-analysis approach to investigate the effect of gene expression level on the clonal expansion process of latently-infected cells during HIV treatment. The results of this analysis show that among the HIV proviruses that integrated into genes, those integrated into poorly expressed genes are more likely to become clonally expanded.
In conclusion, my findings shed light on several important components of the host immune system and their roles in viral control and viral evolution. These findings have implications for the future design of immunotherapies and vaccines against HIV.