Short Communication: Transplacental Nucleoside Analogue Exposure and Mitochondrial Parameters in HIV-Uninfected Children

Brogly, Susan B.; DiMauro, Salvatore; Dyke, Russell B. Van; Williams, Paige L.; Naini, Ali; Libutti, Daniel; Choi, Julia; Chung, M. S.; Gerschenson, Mariana

doi:10.1089/aid.2010.0204

Cited by 33 publications

(28 citation statements)

References 14 publications

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“…1 Of particular concern are the clinical effects of nucleoside reverse-transcriptase inhibitors (NRTIs) on mitochondrial oxidative phosphorylation (OXPHOS) 2 and HIV protease inhibitors (PIs) on lipid and glucose metabolism. [3][4][5] Fatty acid oxidation (FAO) is an intramitochondrial metabolic pathway situated at the crux of mitochondrial OXPHOS, lipid catabolism, and glucose utilization.…”

Section: Introductionmentioning

confidence: 99%

Acylcarnitine Profiles in HIV-Exposed, Uninfected Neonates in the United States

Kirmse

Yao

Hofherr

et al. 2016

AIDS Research and Human Retroviruses

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We sought to determine the prevalence of abnormal acylcarnitine profiles (ACP) in HIV-exposed uninfected (HEU) newborns and to explore the association of abnormal ACP with clinical laboratory outcomes and antiretroviral drug exposures. Clinically, ACP are used to assess for fatty acid oxidation (FAO) dysfunction and normal FAO is necessary for optimal fetal/neonatal growth and development. We analyzed serum ACP in 522 HEU neonates enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS) and evaluated the associations of abnormal ACP with in utero exposure to combination antiretroviral therapy (cART) in logistic regression models, adjusting for maternal demographic, disease, and behavioral characteristics. We evaluated the associations of abnormal ACP with laboratory parameters and measures of neurodevelopment and growth. Of 522 neonates, 89 (17%) had abnormal ACP. In adjusted analyses, in utero exposure to a protease inhibitor (PI) was associated with higher odds of having an abnormal ACP [adjusted odds ratio (aOR) = 2.35, 95% CI: 0.96, 5.76, p = 0.06] with marginal significance while exposure to a nonnucleoside reverse transcriptase inhibitor (NNRTI) was associated with lower odds (aOR = 0.23, 95% CI: 0.07, 0.80, p = 0.02). Mean ALT levels were slightly higher in those with abnormal ACP, but no differences in lactate, glucose, or CPK were observed. ACP status was not associated with neurodevelopment at 1 year or growth at 2 and 3 years of age. Abnormal ACP in HEU neonates are associated with exposure to PIcontaining as opposed to NNRTI-containing antiretroviral (ARV) regimens but are not associated with serious postnatal clinical problems. Further studies are needed to determine the long-term health implications of abnormal acylcarnitine metabolism at birth in HEU children.

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Section: Introductionmentioning

confidence: 99%

Acylcarnitine Profiles in HIV-Exposed, Uninfected Neonates in the United States

Kirmse

Yao

Hofherr

et al. 2016

AIDS Research and Human Retroviruses

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“…Peripheral neuropathy of nucleoside analogues is confirmed to associate with mitochondrial toxicity (Dalakas 2001;Youle 2007). It is easy for nucleoside analogues to penetrate blood-brain barrier and blood-testis barrier (Brogly et al 2011;Pavili et al 2010). In our previous study, we confirmed mtDNA lesions and oxidative damage in the cerebral cortex of AIDS patients with combined antiretroviral therapy (Zhang et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA D-loop AG/TC transition mutation in cortical neurons of mice after long-term exposure to nucleoside analogues

et al. 2015

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With the wide application of combined antiretroviral therapy, the prognosis of human immunodeficiency virus (HIV)-1 infected patient has been significantly improved. However, long-term administration of antiretroviral drugs can result in various drug-associated toxicities. Among them, nucleoside analogues were confirmed to inhibit DNA polymerase gamma, resulting in mitochondrial toxicity. Our previous study indicated that long-term exposure of mice to nucleoside analogue could induce mitochondria DNA (mtDNA) loss in cortical neurons. Herein, we further identify mitochondrial toxicity of four nucleoside analogues (zidovudine (AZT), stavudine (D4T), lamivudine (3TC), and didanosine (DDI)) by cloning and sequencing mtDNA D-loop region in mice neurons captured with laser capture microdissection. The results showed that mutation of neuronal mtDNA D-loop sequences increased in mice treated with each of the four nucleoside analogues for 4 months and D4T and DDI induced more severe D-loop lesion than the other two nucleoside analogues. The major type of D-loop point mutations induced by four nucleoside analogues was transition, in particular of "A→G" and "T→C" transition, but the point transition sites were variable. Our findings suggest that long-term exposure to nucleoside analogue can result in mtDNA D-loop region lesion in mouse cortical neurons.

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“…PBMC mtDNA copies/cell was assayed by absolute quantitative real time PCR as previously published. 20 Each sample and standard were run in duplicate and the results were analyzed with Version 1.5.0 LightCycler 480 software.…”

Section: Laboratory Methodsmentioning

confidence: 99%

Short Communication: The Relationship Between Mitochondrial Dysfunction and Insulin Resistance in HIV-Infected Children Receiving Antiretroviral Therapy

Sharma

Jacobson

Anderson

et al. 2013

AIDS Research and Human Retroviruses

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Mitochondrial abnormalities may lead to metabolic complications in HIV-infected children who have been receiving long-term antiretroviral treatment. We conducted a matched, case-control study comparing 21 HIVinfected children with insulin resistance (cases) to 21 HIV-infected children without insulin resistance (controls) to assess differences in mitochondrial DNA (mtDNA) copies/cell and oxidative phosphorylation NADH dehydrogenase (C1) and cytochrome c oxidase (C4) enzyme activities in peripheral blood mononuclear cells. MtDNA copies/cell tended to be lower in cases, and fasting serum glucose levels were inversely and significantly correlated with C1 enzyme activity, more so in cases. Larger pediatric studies should evaluate mitochondrial etiologies of insulin resistance and determine the role of antiretroviral therapies or HIV infection on mitochondrial dysfunction.

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Short Communication: Transplacental Nucleoside Analogue Exposure and Mitochondrial Parameters in HIV-Uninfected Children

Cited by 33 publications

References 14 publications

Acylcarnitine Profiles in HIV-Exposed, Uninfected Neonates in the United States

Acylcarnitine Profiles in HIV-Exposed, Uninfected Neonates in the United States

Mitochondrial DNA D-loop AG/TC transition mutation in cortical neurons of mice after long-term exposure to nucleoside analogues

Short Communication: The Relationship Between Mitochondrial Dysfunction and Insulin Resistance in HIV-Infected Children Receiving Antiretroviral Therapy

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