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Ofelia A Olivero - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Toxicity in fetal erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine
AIDS Research and Human Retroviruses, 2004Co-Authors: Mariana Gerschenson, S W Harbaugh, J W Harbaugh, Andrea Ceresa, Jaclyn A Shaw, Vi Nguyen, Ember L. Ewings, Kunio Nagashima, Marisa St Claire, Ofelia A OliveroAbstract:This study was designed to investigate fetal Mitochondrial Toxicity in Erythrocebus patas monkeys exposed in utero to zidovudine (AZT) and lamivudine (3TC), and taken at term. Pregnant patas monkeys were given a daily dose of 40 mg AZT (86% of the human daily dose, based on body weight), for the last 10 weeks (50%) of gestation, and a daily dose of 24 mg 3TC (84% of the human daily dose, based on body weight) for the last 4 weeks of gestation. At term, AZT was found to be incorporated into fetal Mitochondrial DNA from skeletal muscle, liver, kidney, and placenta. By transmission electron microscopy (EM) drug-exposed fetal cardiac and skeletal muscle cells showed Mitochondrial membrane compromise, Mitochondrial proliferation, and damaged sarcomeres, while mitochondria in brain cerebrum and cerebellum were morphologically normal. Substantial depletion of oxidative phosphorylation (OXPHOS) Complex I specific activities was observed in heart (87% reduction in mean, p = 0.02) and skeletal muscle (98% reduction...
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Mitochondrial Toxicity in fetal erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine
AIDS Research and Human Retroviruses, 2004Co-Authors: Mariana Gerschenson, S W Harbaugh, J W Harbaugh, Andrea Ceresa, Jaclyn A Shaw, Vi Nguyen, Ember L. Ewings, Kunio Nagashima, Marisa St Claire, Ofelia A OliveroAbstract:This study was designed to investigate fetal Mitochondrial Toxicity in Erythrocebus patas monkeys exposed in utero to zidovudine (AZT) and lamivudine (3TC), and taken at term. Pregnant patas monkeys were given a daily dose of 40 mg AZT (86% of the human daily dose, based on body weight), for the last 10 weeks (50%) of gestation, and a daily dose of 24 mg 3TC (84% of the human daily dose, based on body weight) for the last 4 weeks of gestation. At term, AZT was found to be incorporated into fetal Mitochondrial DNA from skeletal muscle, liver, kidney, and placenta. By transmission electron microscopy (EM) drug-exposed fetal cardiac and skeletal muscle cells showed Mitochondrial membrane compromise, Mitochondrial proliferation, and damaged sarcomeres, while mitochondria in brain cerebrum and cerebellum were morphologically normal. Substantial depletion of oxidative phosphorylation (OXPHOS) Complex I specific activities was observed in heart (87% reduction in mean, p = 0.02) and skeletal muscle (98% reduction in mean, p = 0.002) from drug-exposed fetuses, compared to unexposed fetuses. In addition Complex IV activity was highly depleted (85% reduction in mean, p = 0.004) in skeletal muscle from the drug-exposed fetuses (p = 0.004). Brain cerebrum and cerebellum showed no statistically significant OXPHOS changes with drug exposure. Mitochondrial DNA quantity was substantially depleted (>50%) in heart, skeletal muscle, cerebellum, and cerebrum from drug-exposed fetuses compared to unexposed controls. Overall, the data indicate that significant Mitochondrial damage was observed at birth in monkey fetuses exposed in utero to AZT plus 3TC in a human-equivalent dosing protocol.
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long term Mitochondrial Toxicity in hiv uninfected infants born to hiv infected mothers
Journal of Acquired Immune Deficiency Syndromes, 2003Co-Authors: Miriam C Poirier, Vi Nguyen, Ofelia A Olivero, Rao L Divi, Lena Alharthi, Brettania L Walker, Alan L Landay, Vernon E Walker, Manhattan Charurat, William A BlattnerAbstract:Although children born to HIV-infected (HIV+) women receiving antiretroviral therapy during pregnancy show virtually no adverse clinical effects at birth, the antiretroviral nucleoside analog drugs are known to damage nuclear and Mitochondrial DNA. In this study, biomarkers of Mitochondrial Toxicity and genoToxicity have been examined in a well-characterized sample set consisting of infants born to HIV-uninfected (HIV-) mothers (n = 30), and HIV- infants (n = 20) born to HIV-infected (HIV+) mothers who received either no antiretroviral therapy (n = 10) or zidovudine (3'-azido-3'-deoxythymidine [AZT]) during pregnancy (n = 10). DNA from cord blood leukocytes and peripheral blood leukocytes taken at 1 and 2 years of age was examined for loss of Mitochondrial DNA (mtDNA) and telomere integrity. Telomere length, a measure of nuclear DNA damage, was the same in all infants at birth and at age 1 year. The quantity of mtDNA was assessed relative to nuclear DNA using a polymerase chain reaction-based chemiluminescence detection (PCR-CID) method that determined Mitochondrial D Loop gene copies relative to nuclear 18S RNA gene copies by comparison with a standard curve. MtDNA quantity was expressed as a ratio of gene copy numbers. In infants of uninfected mothers (AZT-/HIV-) at the three time points, the ratios were 442 to 515, whereas in infants of untreated AZT-/HIV+ mothers the ratios were 261 to 297, and in infants of AZT-treated (AZT+/HIV+) mothers the ratios were 146 to 203. At all three time points, differences between the AZT-/HIV- group and the two HIV+ groups were statistically significant (p <.05), and differences between the AZT-/HIV+ and AZT+/HIV+ groups were also statistically significant (p <.05), demonstrating that AZT exposure causes a persistent depletion of mtDNA. The study shows that children of HIV+ mothers are at risk for Mitochondrial damage that is further increased in infants of mothers receiving AZT during pregnancy.
Mariana Gerschenson - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Toxicity in fetal erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine
AIDS Research and Human Retroviruses, 2004Co-Authors: Mariana Gerschenson, S W Harbaugh, J W Harbaugh, Andrea Ceresa, Jaclyn A Shaw, Vi Nguyen, Ember L. Ewings, Kunio Nagashima, Marisa St Claire, Ofelia A OliveroAbstract:This study was designed to investigate fetal Mitochondrial Toxicity in Erythrocebus patas monkeys exposed in utero to zidovudine (AZT) and lamivudine (3TC), and taken at term. Pregnant patas monkeys were given a daily dose of 40 mg AZT (86% of the human daily dose, based on body weight), for the last 10 weeks (50%) of gestation, and a daily dose of 24 mg 3TC (84% of the human daily dose, based on body weight) for the last 4 weeks of gestation. At term, AZT was found to be incorporated into fetal Mitochondrial DNA from skeletal muscle, liver, kidney, and placenta. By transmission electron microscopy (EM) drug-exposed fetal cardiac and skeletal muscle cells showed Mitochondrial membrane compromise, Mitochondrial proliferation, and damaged sarcomeres, while mitochondria in brain cerebrum and cerebellum were morphologically normal. Substantial depletion of oxidative phosphorylation (OXPHOS) Complex I specific activities was observed in heart (87% reduction in mean, p = 0.02) and skeletal muscle (98% reduction...
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Mitochondrial Toxicity in fetal erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine
AIDS Research and Human Retroviruses, 2004Co-Authors: Mariana Gerschenson, S W Harbaugh, J W Harbaugh, Andrea Ceresa, Jaclyn A Shaw, Vi Nguyen, Ember L. Ewings, Kunio Nagashima, Marisa St Claire, Ofelia A OliveroAbstract:This study was designed to investigate fetal Mitochondrial Toxicity in Erythrocebus patas monkeys exposed in utero to zidovudine (AZT) and lamivudine (3TC), and taken at term. Pregnant patas monkeys were given a daily dose of 40 mg AZT (86% of the human daily dose, based on body weight), for the last 10 weeks (50%) of gestation, and a daily dose of 24 mg 3TC (84% of the human daily dose, based on body weight) for the last 4 weeks of gestation. At term, AZT was found to be incorporated into fetal Mitochondrial DNA from skeletal muscle, liver, kidney, and placenta. By transmission electron microscopy (EM) drug-exposed fetal cardiac and skeletal muscle cells showed Mitochondrial membrane compromise, Mitochondrial proliferation, and damaged sarcomeres, while mitochondria in brain cerebrum and cerebellum were morphologically normal. Substantial depletion of oxidative phosphorylation (OXPHOS) Complex I specific activities was observed in heart (87% reduction in mean, p = 0.02) and skeletal muscle (98% reduction in mean, p = 0.002) from drug-exposed fetuses, compared to unexposed fetuses. In addition Complex IV activity was highly depleted (85% reduction in mean, p = 0.004) in skeletal muscle from the drug-exposed fetuses (p = 0.004). Brain cerebrum and cerebellum showed no statistically significant OXPHOS changes with drug exposure. Mitochondrial DNA quantity was substantially depleted (>50%) in heart, skeletal muscle, cerebellum, and cerebrum from drug-exposed fetuses compared to unexposed controls. Overall, the data indicate that significant Mitochondrial damage was observed at birth in monkey fetuses exposed in utero to AZT plus 3TC in a human-equivalent dosing protocol.
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Mitochondrial dysfunction and antiretroviral nucleoside analog toxicities what is the evidence
Mitochondrion, 2002Co-Authors: Tamir Dagan, Craig Sable, June Bray, Mariana GerschensonAbstract:Mitochondrial dysfunction has been associated with long-term toxicities of human immunodeficiency virus (HIV) therapy, particularly with the nucleoside analog reverse transcriptase inhibitors (NRTIs). Lactic acidosis, hepatic steatosis, myopathies, cardiomyopathies, neuropathies, and lipodystrophy are frequently attributed to Mitochondrial Toxicity. Since Mitochondrial Toxicity could pose a major threat to the long-term success of HIV therapy, the scientific evidence underlying an association between Mitochondrial Toxicity and antiretroviral therapies, must be carefully examined. There is some data to support the association between NRTIs and mitochondria dysfunction. In this review, we examine human, animal, and in vitro data implicating Mitochondrial dysfunction as the causal mechanism of NRTI-associated Toxicity in HIV-infected patients.
Baruch D. Kuppermann - One of the best experts on this subject based on the ideXlab platform.
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safety profiles of anti vegf drugs bevacizumab ranibizumab aflibercept and ziv aflibercept on human retinal pigment epithelium cells in culture
British Journal of Ophthalmology, 2014Co-Authors: Deepika Malik, Mohamed Tarek, Claudio Ramirez, David S. Boyer, Javier Caceres Del Carpio, Cristina M Kenney, Baruch D. KuppermannAbstract:PURPOSE: To compare the safety profiles of antivascular endothelial growth factor (VEGF) drugs ranibizumab, bevacizumab, aflibercept and ziv-aflibercept on retinal pigment epithelium cells in culture. METHODS: Human retinal pigment epithelium cells (ARPE-19) were exposed for 24 h to four anti-VEGF drugs at 1/2×, 1×, 2× and 10× clinical concentrations. Cell viability and Mitochondrial membrane potential assay were performed to evaluate early apoptotic changes and rate of overall cell death. RESULTS: Cell viability decreased at 10× concentrations in bevacizumab (82.38%, p=0.0001), aflibercept (82.68%, p=0.0002) and ziv-aflibercept (77.25%, p<0.0001), but not at lower concentrations. However, no changes were seen in cell viability in ranibizumab-treated cells at all concentrations including 10×. Mitochondrial membrane potential was slightly decreased in 10× ranibizumab-treated cells (89.61%, p=0.0006) and 2× and 10× aflibercept-treated cells (88.76%, 81.46%; p<0.01, respectively). A larger reduction in Mitochondrial membrane potential was seen at 1×, 2× and 10× concentrations of bevacizumab (86.53%, 74.38%, 66.67%; p<0.01) and ziv-aflibercept (73.50%, 64.83% and 49.65% p<0.01) suggestive of early apoptosis at lower doses, including the clinical doses. CONCLUSIONS: At clinical doses, neither ranibizumab nor aflibercept produced evidence of Mitochondrial Toxicity or cell death. However, bevacizumab and ziv-aflibercept showed mild Mitochondrial Toxicity at clinically relevant doses.
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Safety profiles of anti-VEGF drugs: bevacizumab, ranibizumab, aflibercept and ziv-aflibercept on human retinal pigment epithelium cells in culture
British Journal of Ophthalmology, 2014Co-Authors: Deepika Malik, Mohamed Tarek, Javier Caceres Del Carpio, Claudio Ramirez, David S. Boyer, M. Cristina Kenney, Baruch D. KuppermannAbstract:Purpose To compare the safety profiles of antivascular endothelial growth factor (VEGF) drugs ranibizumab, bevacizumab, aflibercept and ziv-aflibercept on retinal pigment epithelium cells in culture. Methods Human retinal pigment epithelium cells (ARPE-19) were exposed for 24 h to four anti-VEGF drugs at 1/2×, 1×, 2× and 10× clinical concentrations. Cell viability and Mitochondrial membrane potential assay were performed to evaluate early apoptotic changes and rate of overall cell death. Results Cell viability decreased at 10× concentrations in bevacizumab (82.38%, p=0.0001), aflibercept (82.68%, p=0.0002) and ziv-aflibercept (77.25%, p Conclusions At clinical doses, neither ranibizumab nor aflibercept produced evidence of Mitochondrial Toxicity or cell death. However, bevacizumab and ziv-aflibercept showed mild Mitochondrial Toxicity at clinically relevant doses.
Yvonne Will - One of the best experts on this subject based on the ideXlab platform.
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validation of a hts amenable assay to detect drug induced Mitochondrial Toxicity in the absence and presence of cell death
Toxicology in Vitro, 2013Co-Authors: Rachel Swiss, Sashi Nadanaciva, Andrew L Niles, James J Cali, Yvonne WillAbstract:Abstract Drug-induced Mitochondrial dysfunction is known to contribute to late stage compound attrition. Recently, assays that identify Mitochondrial dysfunction have been developed but many require expensive reagents, specialized equipment, or specialized expertise such as isolation of mitochondria. Here, we validate a new 384-well format cell-based dual parameter assay that uses commonly available detection methods to measure both Mitochondrial Toxicity and cytoToxicity. In our initial evaluation, antimycin A, CCCP, nefazodone, flutamide, and digitonin were tested in K562 cells in both glucose- and galactose-supplemented media with a 2 h incubation. The assay was able to correctly differentiate these compounds into Mitochondrial toxicants and non-Mitochondrial toxicants, and had excellent reproducibility. We next tested 74 compounds in K562 cells in both types of media and show that the assay was able to correctly identify some of the compounds as Mitochondrial toxicants. Moreover, the assay could be simplified, without loss of information, by using K562 cells in galactose-containing medium alone. This simple, robust assay can be positioned as a rapid, early readout of Mitochondrial and cellular Toxicity. However, since the assay fails to identify some Mitochondrial toxicants, further assays may be required to detect Mitochondrial Toxicity once lead compounds have been selected.
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a high throughput dual parameter assay for assessing drug induced Mitochondrial dysfunction provides additional predictivity over two established Mitochondrial Toxicity assays
Toxicology in Vitro, 2013Co-Authors: James Hynes, Sashi Nadanaciva, Rachel Swiss, Conn Carey, Sinead Kirwan, Yvonne WillAbstract:Mitochondrial Toxicity is a major reason for safety-related compound attrition and post-market drug withdrawals, highlighting the necessity for higher-throughput screens that can identify this mechanism of Toxicity during the early stages of drug discovery. Here, we present the validation of a 384-well dual parameter plate-based assay capable of measuring oxygen consumption and extracellular acidification in intact cells simultaneously. The assay showed good reproducibility and robustness and is suitable for use with both suspension cells and adherent cells. To determine if the assay provides additional value in detecting Mitochondrial Toxicity over existing platforms, 200 commercially available drugs were tested in the assay using HL60 suspension cells as well as in two conventional Mitochondrial Toxicity assays: an oxygen consumption assay that uses isolated mitochondria and a cell-based assay that uses HepG2 cells grown in glucose and galactose media. The combination of the dual parameter assay and the isolated Mitochondrial oxygen consumption assay identified more compounds that caused Mitochondrial impairment than any other combination of the three assays or each of the three assays on its own. Furthermore, novel information was obtained from the dual parameter assay on drugs not previously reported to cause Mitochondrial impairment.
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the significance of Mitochondrial Toxicity testing in drug development
Drug Discovery Today, 2007Co-Authors: James A Dykens, Yvonne WillAbstract:Mitochondrial dysfunction is increasingly implicated in the etiology of drug-induced toxicities. Members of diverse drug classes undermine Mitochondrial function, and among the most potent are drugs that have been withdrawn from the market, or have received Black Box warnings from the FDA. To avoid Mitochondrial liabilities, routine screens need to be positioned within the drug-development process. Assays for Mitochondrial function, cell models that better report Mitochondrial impairment, and new animal models that more faithfully reflect clinical manifestations of Mitochondrial dysfunction are discussed in the context of how such data can reduce late stage attrition of drug candidates and can yield safer drugs in the future.
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target identification of drug induced Mitochondrial Toxicity using immunocapture based oxphos activity assays
Toxicology in Vitro, 2007Co-Authors: Sashi Nadanaciva, Autumn Bernal, Robert Aggeler, Roderick A Capaldi, Yvonne WillAbstract:Mitochondrial dysfunction has been shown to be a pharmacotoxicological response to a variety of currently-marketed drugs. In order to reduce attrition due to Mitochondrial Toxicity, high throughput-applicable screens are needed for early stage drug discovery. We describe, here, a set of immunocapture based assays to identify compounds that directly inhibit four of the oxidative phosphorylation (OXPHOS) complexes: I, II, IV, and V. Intra- and inter-assay variation were determined and specificity tested by using classical Mitochondrial inhibitors. Twenty drugs, some with known Mitochondrial Toxicity and others with no known Mitochondrial liability, were studied. Direct inhibition of one or more of the OXPHOS complexes was identified for many of the drugs. Novel information was obtained for several drugs including ones with previously unknown effects on oxidative phosphorylation. A major advantage of the immunocapture approach is that it can be used throughout drug screening from early compound evaluation to clinical trials.
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strategies to reduce late stage drug attrition due to Mitochondrial Toxicity
Expert Review of Molecular Diagnostics, 2007Co-Authors: James A Dykens, Lisa D Marroquin, Yvonne WillAbstract:Mitochondrial dysfunction is increasingly implicated in the etiology of drug-induced toxicities and negative side-effect profiles. Early identification of Mitochondrial liabilities for new chemical entities is therefore crucial for avoiding late-stage attrition during drug development. Limitations of traditional methods for assessing Mitochondrial dysfunction have discouraged routine evaluation of Mitochondrial liabilities. To circumvent this bottleneck, a high-throughput screen has been developed that measures oxygen consumption; one of the most informative parameters for the assessment of Mitochondrial status. This technique has revealed that some, but not all, members of many major drug classes have Mitochondrial liabilities. This dichotomy encourages optimism that efficacy can be disassociated from Mitochondrial Toxicity, resulting in safer drugs in the future.
Vi Nguyen - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Toxicity in fetal erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine
AIDS Research and Human Retroviruses, 2004Co-Authors: Mariana Gerschenson, S W Harbaugh, J W Harbaugh, Andrea Ceresa, Jaclyn A Shaw, Vi Nguyen, Ember L. Ewings, Kunio Nagashima, Marisa St Claire, Ofelia A OliveroAbstract:This study was designed to investigate fetal Mitochondrial Toxicity in Erythrocebus patas monkeys exposed in utero to zidovudine (AZT) and lamivudine (3TC), and taken at term. Pregnant patas monkeys were given a daily dose of 40 mg AZT (86% of the human daily dose, based on body weight), for the last 10 weeks (50%) of gestation, and a daily dose of 24 mg 3TC (84% of the human daily dose, based on body weight) for the last 4 weeks of gestation. At term, AZT was found to be incorporated into fetal Mitochondrial DNA from skeletal muscle, liver, kidney, and placenta. By transmission electron microscopy (EM) drug-exposed fetal cardiac and skeletal muscle cells showed Mitochondrial membrane compromise, Mitochondrial proliferation, and damaged sarcomeres, while mitochondria in brain cerebrum and cerebellum were morphologically normal. Substantial depletion of oxidative phosphorylation (OXPHOS) Complex I specific activities was observed in heart (87% reduction in mean, p = 0.02) and skeletal muscle (98% reduction...
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Mitochondrial Toxicity in fetal erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine
AIDS Research and Human Retroviruses, 2004Co-Authors: Mariana Gerschenson, S W Harbaugh, J W Harbaugh, Andrea Ceresa, Jaclyn A Shaw, Vi Nguyen, Ember L. Ewings, Kunio Nagashima, Marisa St Claire, Ofelia A OliveroAbstract:This study was designed to investigate fetal Mitochondrial Toxicity in Erythrocebus patas monkeys exposed in utero to zidovudine (AZT) and lamivudine (3TC), and taken at term. Pregnant patas monkeys were given a daily dose of 40 mg AZT (86% of the human daily dose, based on body weight), for the last 10 weeks (50%) of gestation, and a daily dose of 24 mg 3TC (84% of the human daily dose, based on body weight) for the last 4 weeks of gestation. At term, AZT was found to be incorporated into fetal Mitochondrial DNA from skeletal muscle, liver, kidney, and placenta. By transmission electron microscopy (EM) drug-exposed fetal cardiac and skeletal muscle cells showed Mitochondrial membrane compromise, Mitochondrial proliferation, and damaged sarcomeres, while mitochondria in brain cerebrum and cerebellum were morphologically normal. Substantial depletion of oxidative phosphorylation (OXPHOS) Complex I specific activities was observed in heart (87% reduction in mean, p = 0.02) and skeletal muscle (98% reduction in mean, p = 0.002) from drug-exposed fetuses, compared to unexposed fetuses. In addition Complex IV activity was highly depleted (85% reduction in mean, p = 0.004) in skeletal muscle from the drug-exposed fetuses (p = 0.004). Brain cerebrum and cerebellum showed no statistically significant OXPHOS changes with drug exposure. Mitochondrial DNA quantity was substantially depleted (>50%) in heart, skeletal muscle, cerebellum, and cerebrum from drug-exposed fetuses compared to unexposed controls. Overall, the data indicate that significant Mitochondrial damage was observed at birth in monkey fetuses exposed in utero to AZT plus 3TC in a human-equivalent dosing protocol.
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long term Mitochondrial Toxicity in hiv uninfected infants born to hiv infected mothers
Journal of Acquired Immune Deficiency Syndromes, 2003Co-Authors: Miriam C Poirier, Vi Nguyen, Ofelia A Olivero, Rao L Divi, Lena Alharthi, Brettania L Walker, Alan L Landay, Vernon E Walker, Manhattan Charurat, William A BlattnerAbstract:Although children born to HIV-infected (HIV+) women receiving antiretroviral therapy during pregnancy show virtually no adverse clinical effects at birth, the antiretroviral nucleoside analog drugs are known to damage nuclear and Mitochondrial DNA. In this study, biomarkers of Mitochondrial Toxicity and genoToxicity have been examined in a well-characterized sample set consisting of infants born to HIV-uninfected (HIV-) mothers (n = 30), and HIV- infants (n = 20) born to HIV-infected (HIV+) mothers who received either no antiretroviral therapy (n = 10) or zidovudine (3'-azido-3'-deoxythymidine [AZT]) during pregnancy (n = 10). DNA from cord blood leukocytes and peripheral blood leukocytes taken at 1 and 2 years of age was examined for loss of Mitochondrial DNA (mtDNA) and telomere integrity. Telomere length, a measure of nuclear DNA damage, was the same in all infants at birth and at age 1 year. The quantity of mtDNA was assessed relative to nuclear DNA using a polymerase chain reaction-based chemiluminescence detection (PCR-CID) method that determined Mitochondrial D Loop gene copies relative to nuclear 18S RNA gene copies by comparison with a standard curve. MtDNA quantity was expressed as a ratio of gene copy numbers. In infants of uninfected mothers (AZT-/HIV-) at the three time points, the ratios were 442 to 515, whereas in infants of untreated AZT-/HIV+ mothers the ratios were 261 to 297, and in infants of AZT-treated (AZT+/HIV+) mothers the ratios were 146 to 203. At all three time points, differences between the AZT-/HIV- group and the two HIV+ groups were statistically significant (p <.05), and differences between the AZT-/HIV+ and AZT+/HIV+ groups were also statistically significant (p <.05), demonstrating that AZT exposure causes a persistent depletion of mtDNA. The study shows that children of HIV+ mothers are at risk for Mitochondrial damage that is further increased in infants of mothers receiving AZT during pregnancy.