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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
7K23AI073141-03
Application #
7787308
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Zhang, Hao
Project Start
2007-09-01
Project End
2012-07-31
Budget Start
2008-09-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$107,612
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Sinxadi, Phumla Z; Dave, Joel A; Samuels, David C et al. (2013) Mitochondrial genomics and antiretroviral therapy-associated metabolic complications in HIV-infected Black South Africans: a pilot study. AIDS Res Hum Retroviruses 29:1031-9
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Haas, David W; Kuritzkes, Daniel R; Ritchie, Marylyn D et al. (2011) Pharmacogenomics of HIV therapy: summary of a workshop sponsored by the National Institute of Allergy and Infectious Diseases. HIV Clin Trials 12:277-85
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