The applicant's long-term goals are to independently conduct clinical trials related to adult HIV care and treatment in the African context, particularly with respect to HAART tolerability and toxicity. Nucleoside analogue reverse transcriptase inhibitors (NRTIs) are effective antiretroviral therapies for the treatment of HIV-1 infected adults and they will likely remain a critical component of ART regimens in resource-poor settings. However, their ability to inhibit human mitochondrial polymerase-gamma has been associated with several long-term mitochondrial toxicities; these include lactic acidosis, pancreatitis, peripheral neuropathy, and peripheral fat wasting/atrophy. Some studies provide preliminary evidence for the role of certain genes/genetic pathways in mediating this toxicity. Preliminary experience in Botswana and South Africa has shown that rates of mitochondrial toxicity (and specifically lactic acidosis) appear to be higher than that which has been reported elsewhere. The risk for these mitochondrial toxicities appears to be related to: (i) gender (seen predominantly in females), (ii) body weight (seen primarily in those who are overweight/obese), and (iii) the specific NRTI or combination of NRTIs they are receiving. The specific epidemiologic, clinical, and genetic risk factors associated with this apparent increased risk are unknown, we therefore propose the following Specific Aims: 1. Within the context of an existing HAART-treated cohort, we will determine the clinical factors and laboratory values associated with the development of mitochondrial toxicity among HAART-treated adults in Botswana. 2. Evaluating existing specimens from cohort participants, and utilizing case-control methodology, we will identify subsets of genes that may be associated with mitochondrial toxicity using newer RNA gene expression profiling techniques focusing on specific gene sets. 3. Based on information obtained in Aims 1 and 2; we will identify mitochondrial, drug metabolism, and other single nucleotide polymorphism (SNP) variants that may alter the expression of relevant genes involved in mitochondrial function and be associated with the development of mitochondrial toxicity. ? ? ?
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