| Summary: | <p>Since human immunodeficiency virus type 1 (HIV-1) was discovered over thirty years ago, much effort has been expended developing a vaccine. Unfortunately, all randomised clinical trials have failed except one, which may have shown a slight beneficial result. In this thesis, I study the CD8+ cytotoxic T Lymphocyte (CTL) immune response against p24 group-specific antigen (Gag), a prime candidate for vaccine boosting. This immune response is associated with long-term survival in some patients with beneficial HLA variants. Independently of HLA variant, the number of Gag epitopes targeted by the patient’s CTL response is associated with lower viral loads.</p> <p>In the first three chapters, I considered the HIV-1M subtype-specific sites; the current paradigm is that these differences between the consensus sequences of HIV-1M subtypes are the result of founder effects. However, I use Chapter Two to show that these sites are strongly associated with the patients' HLA variants, suggesting a role for CTL selection in subtype-diversification through epitope processing escape. </p> <p>In Chapter Three, I show that as the United States HIV-infected population became increasingly African-American over the last two decades, the amino acids in the subtype-specific sites became less typical of HIV-1M subtype B, and appeared to become increasingly similar to HIV sequences found in Africa. Together with the results from Chapter Two this suggests that viral adaptation to population HLA frequencies may drive subtype diversification.</p> <p>In Chapter Four, I show that patients with beneficial HLA variants select for the outgrowth of HIV-1 recombinants, possibly because recombination allows for large fitness jumps and the large-scale, rapid spreading of escape and compensatory mutations. In Chapter Five, I show how repeated recombinations could lead to HIV-1 outgrowths in the presence of beneficial HLA types. If viral recombination can abrogate the natural CTL response, it is likely that a vaccine-boosted immune response can also be evaded. Because recombination over large phylogenetic distances is a likely avenue towards HIV vaccine escape, I recommend that patients exposed to many strains should be monitored closely. </p> <p> In Chapter Six I use a clade of betaretroviruses, which are related to HIV, to study viral cross-species transmission between mammals over the last 40 million years. I found strong evidence for transmissions between mammals separated by large geographical and phylogenetic distances, and evidence suggesting that rodents play a central role in the transmission of betaretroviruses, and that host phylogenetic relatedness is associated with cross-species transmission in this clade.</p>
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