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.
| Identifer | oai:union.ndltd.org:ADTP/221844 |
| Date | January 2006 |
| Creators | craig.pace@murdoch.edu.au, Craig Stuart Pace |
| Publisher | Murdoch University |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://www.murdoch.edu.au/goto/CopyrightNotice, Copyright Craig Stuart Pace |
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