17th International AIDS Conference Mexico City, Mexico - August 13 - 18, 2008

HAART EFFECTS ON MITOCHONDRIAL FUNCTION IN HUMAN BRAIN CELLS

Int Conf AIDS. 2008 Aug 13-18;17 Abstract No. MoAa0103

C. Kim, J. Lloyd, D. Libutti, M. Gerschenson
University of Hawaii at Manoa, Honolulu, United States

BACKGROUND: Advances in highly active antiretroviral therapy (HAART) have led to improved survival for HIV-infected patients, however, HIV-associated dementia (HAD) continues to be a complication. Nucleoside reverse transcriptase inhibitors (NRTI), a key component of HAART, are associated with mitochondrial (mt) DNA depletion and/or changes in the expression of oxidative phosphorylation genes, which in turn could lead to cellular changes in ATP levels. We have developed a cell model to further elucidate the effects of HAART on mitochondrial function in human neurons and astrocytes grown in vitro.

METHODS: Human primary cortical neurons (ATCC, Manassas VA) or astrocytes (Cambrex, Baltimore MD) were treated (n=3) for 14-18 days with human cerebrospinal fluid equivalent doses of 0.2 μM AZT, 0.75 μM 3TC, and 0.03 μM lopinavir/ritonavir and compared to untreated (n=4). Mitochondrial function was analyzed by measuring mtDNA copies/cell and mtRNA involved in oxidative phosphorylation (Cytochrome-b (CytB), NADH Dehydrogenase Subunit I (ND1) and VI (ND6)) relative to the nuclear gene ribosomal L13 using real-time PCR. ATP concentration was quantitated using bioluminescence. Statistical analysis was conducted using a Student’s t-test and a Pearson’s Product Moment Correlation.

RESULTS: Neuronal mtDNA levels were increased in AZT/3TC/lopinavir/ritonavir treated compared to controls at days 14, 16, and 18: 4258.7 ± 738.9 vs 2373.5 ± 565.2 copies/cell (p=0.012), 4706.3 ± 315 vs 2723.3 ± 853.3 copies/cell (p=0.009), and 4868.6 ± 763.6 vs 2709 ± 650.8 copies/cell (p=0.005). Neuronal mtRNA CytB/L13 and ND1/L13 were decreased in the experimental group compared to controls at day-11: 4.8 ± 1.2 vs 10.3 ± 2.9 CytB/L13 (p=0.022) and 3.7 ± 0.7 vs 9.7 ± 0.8 ND1/L13 (p=0.001). Neuronal ATP levels were increased at day-11 in the experimental group compared to controls (175.1 ± 12.5 vs 98.1 ± 32.5 nmol/mg, p=0.36). Astrocytes were unaffected by drug treatment.

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2008-08-13
MoAa0103

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