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The influence of APOBEC3G and deoxythymidylate kinase genetic diversity on HIV-1 hypermutation and response to treatment

Pace, Craig Stuart (2006) The influence of APOBEC3G and deoxythymidylate kinase genetic diversity on HIV-1 hypermutation and response to treatment. PhD thesis, Murdoch University.

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This thesis addresses two important topics in HIV-1 medicine; (i) the clinical relevance of pre-treatment G-A hypermutation and the contribution of host and viral genetics to its development and; (ii) the influence of genetic variation in host enzymes responsible for antiretroviral drug metabolism on response to therapy. These themes are outlined below.

HIV-1 Hypermutation
At present, limited data exists regarding the relative roles of host encoded cytidine deaminases APOBEC3G and APOBEC3F in promoting G-A hypermutation of HIV-1 proviral DNA in vivo, nor the clinical relevance of hypermutation or the influence of genetic diversity of the APOBEC3G locus and of the viral encoded vif protein that counteracts the action of APOBEC3G. The analyses contained within this thesis demonstrate that within the WA HIV cohort, clinically relevant hypermutation is restricted to a minority of individuals and is mediated predominantly by APOBEC3G. In this study, the presence of HIV-1 hypermutation had a substantially greater effect on plasma viremia than other known host antiviral factors such as CCR5D32 or specific HLA-B alleles. Furthermore, the considerable genetic diversity of the vif gene is likely to make a greater contribution to the development of hypermutation than the limited genetic diversity of the APOBEC3G gene in Caucasians. These data indicate that G-A hypermutation is a clinically relevant phenomenon and may provide a fresh perspective to the area of HIV/AIDS therapies.

Genetic Determinant of HIV-1 Treatment Response
Thymidine kinase 2 (TK2) and thymidylate kinase (dTMPK) are rate limiting enzymes for the metabolism of the antiretrovirals d4T and AZT, respectively, and are thus central to the antiviral efficacy and toxicity of these agents. However, the genetic diversity of TK2 and dTMPK and their influence on toxicities associated with their use is largely unknown. The results discussed in this thesis indicate that in contrast to the highly conserved TK2 locus, the dTMPK locus of Caucasian individuals, including regulatory regions potentially influencing transcription and translation, is considerably polymorphic and organised into five common haplotypes. The results regarding the contribution of dTMPK genetic variation to toxicities associated with AZT therapy are encouraging. A common dTMPK haplotype had significant, albeit modest, effect on haematological parameters (haemoglobin and mean corpuscular volume) in HIV-infected patients, although no AZT-specific treatment effect was observed in this relatively haematologically stable cohort. In addition, another common dTMPK haplotype provided significant protection against AZT-induced adipocyte mtDNA depletion in a pilot study of AZT- and d4T-treated individuals. The dTMPK haplotypes characterised in this thesis should facilitate further studies regarding dTMPK genetic variation in HIV-1 infection and response to treatment, which are warranted from the clinical results presented herein.

Item Type: Thesis (PhD)
Murdoch Affiliation: School of Biological Sciences and Biotechnology
Supervisor(s): Mallal, Simon
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