Evidence of Nucleoside Analogue Reverse Transcriptase Inhibitor–Associated Genetic and Structural Defects of Mitochondria in Adipose Tissue of HIV-Infected Patients

Walker, Ulrich A.; Bickel, Markus; Volksbeck, Severine I. Lütke; Ketelsen, Uwe‐Peter; Schöfer, Helmut; Setzer, Bernhard; Venhoff, Nils; Rickerts, Volker; Staszewski, Schlomo

doi:10.1097/00126334-200202010-00002

Cited by 60 publications

(98 citation statements)

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“…Indeed, in situ hybridization studies in patients with proven mitochondrial cytopathies failed to establish an in vivo threshold necessary for mtDNA mutations to trigger a biochemical dysfunction in clinically affected tissue. 20 It is also interesting to note that the magnitude of mtDNA depression was similar in adipose tissue of patients suffering from HIV-associated lipoatrophy 14 and in hepatic tissue of inherited mtDNA replication defects with liver failure. 21 Our investigations do not demonstrate a clear relationship between mtDNA depletion in hepatic tissue and an increase in serum lactate, but it is important to note that lactate levels were normal in virtually all patients.…”

Section: Discussionmentioning

confidence: 93%

“…The second aliquot of the liver biopsy (4 mm) was immediately frozen and stored at Ϫ70°C until shipment on dry ice for centralized and blinded mtDNA measurements by quantitative Southern blot analysis as described previously. 5,14,15 mtDNA was probed with a 12.9-kb pair, random-prime digoxigenin-labeled fragment, spanning nucleotide positions 3470 and 16379 of human mtDNA; nuclear DNA (nDNA) was simultaneously detected with a second probe, directed against the multicopy 18S ribosomal DNA gene. The intensities of the mtDNA and nDNA signals were densitometrically quantified using Scion-image (Scion Corporation, Frederick, MD), and mtDNA was normalized for nDNA-content by calculating the mtDNA/nDNA ratio.…”

Section: Methodsmentioning

confidence: 99%

“…The mtDNA/nDNA measurements were reliable with an interrun variation of 20%; large variations in the amount of DNA loaded onto the gel do not influence the result. 14,15 Southern blot analysis was also used to screen for large-scale mtDNA deletions.…”

Section: Methodsmentioning

confidence: 99%

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Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine

et al. 2004

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A ntiretroviral therapy (ART) has significantly decreased the HIV-associated morbidity and mortality in industrialized countries. 1 ART usually consists of a combination of two nucleoside analogue reverse transcriptase inhibitors (NRTIs) with either protease inhibitors (PIs) or a nonnucleoside reverse transcriptase inhibitor (NNRTI), or of three NRTIs. 2 With prolonged exposure to antiretroviral drugs, clinicians became aware of long-term side effects of individual ART components. Many adverse effects of the NRTI class of anti-HIV drugs are now related to the fact that NRTIs undergo intracellular triphosphorylation, then inhibit the replication of mitochondrial DNA (mtDNA) by interacting with gamma-polymerase. 3 In vitro studies point toward differences between the potencies of the individual NRTIs in depleting mtDNA, with the socalled "D drugs" zalcitabine (ddC), didanosine (ddI), and stavudine (d4T) being relatively strong inhibitors of polymerase-gamma compared with the other currently licensed nucleoside analogues (so-called "non-D drugs"). 4,5 Studies performed in vitro and in animals suggest that depletion of mtDNA may represent an underlying mechanism of NRTI-related hepatic side effects in HIV patients. [5][6][7] Cell models and animal data, however, have limitations in predicting clinical toxicities, partly because Abbreviations: ART, antiretroviral therapy; NRTI, nucleoside analogue reverse transcriptase inhibitor; PI, protease inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; mtDNA, mitochondrial DNA; ddC, zalcitabine; ddI, didanosine; d4T, stavudine; HCV, hepatitis C virus; nDNA, nuclear DNA; ULN, upper limit of normal; ALT, alanine aminotranferase. From

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Section: Discussionmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

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Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine

et al. 2004

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“…These findings were consistent with those of previous studies in other ethnic groups. 9,20,29,38,39 In contrast, age, transmission route, and CD4 counts pre-ART and at 1 year post-ART did not significantly affect the incidence of LA or LD (Table 2).…”

Section: Incidences Of La And/or Ld In Hiv-1-infected Thai Patients Umentioning

confidence: 93%

Polymorphisms inFasGene Is Associated with HIV-Related Lipoatrophy in Thai Patients

Likanonsakul

Rattanatham

Feangvad

et al. 2013

AIDS Research and Human Retroviruses

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The present study aimed to evaluate the role of genetic polymorphisms in the emergence of lipoatrophy or lipodystrophy in HIV-infected patients with antiretroviral therapy (ART) in Thailand. Position 455 upstream of the Apolipoprotein C3 gene (ApoC3 T-455C, rs2854116), codon 64 of the Beta3 adrenergic receptor gene (ARb3 Tcod64C, rs4994), and position 670 upstream of the Fas gene (Fas A-670G, rs1800682) were genotyped in 829 HIV-infected Thai patients who had started ART. Crude and adjusted incidence rate ratios (IRR) were calculated using Poisson regression. The serum levels of cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were also analyzed. Multivariate analysis revealed an association between the Fas -670AA genotype, but not the ApoC3 -455 or ARb3 cod64 genotypes, with the incidence of lipoatrophy after adjusting for gender and stavudine (d4T)-containing regimens (IRR = 1.72, 95% CI = 1.20-2.45, p = 0.003). However, ApoC3 -455C homozygous patients showed elevated serum levels of triglycerides, while this genotype did not affect serum total cholesterol, HDL, or LDL levels in patients with lipoatrophy or lipodystrophy. In contrast, the ARb3 cod64 genotype did not show any significant association with the serum levels of cholesterol, triglycerides, HDL, or LDL. In conclusion, Fas -670AA affected the incidence of lipoatrophy in HIV-1-infected Thai patients, while the ApoC3 -455C allele affected the serum levels of triglycerides. These results confirmed the role of genetics in the development of ART-related metabolic disorders.

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“…In vitro data suggest that clinically relevant concentrations of some NRTIs impair DNA polymerase-gamma and therefore interfere with the replication of mitochondrial DNA (mtDNA) (Martin et al, 1994). Consistent with such mitochondrial toxicity, reduced copy numbers of mtDNA (mtDNA-depletion) were found in HIV-infected individuals treated with NRTIs (mostly stavudine) and linked with increased adipocyte apoptosis and ultrastructural abnormalities of adipocyte mitochondria (Walker et al, 2002;Nolan et al, 2003).…”

Section: Introductionmentioning

confidence: 97%

Uridine supplementation in HIV lipoatrophy: pilot trial on safety and effect on mitochondrial indices

et al. 2007

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Objectives-Uridine abrogates mitochondrial toxicities of nucleoside reverse transcriptase inhibitor in adipocyte cell culture. We aim to study the effect of uridine supplementation on human adipocyte mitochondrial DNA (mtDNA) levels in subjects with human immunodeficiency (HIV) lipoatrophy.Methods-Sixteen patients with lipoatrophy on stavudine-containing antiretroviral therapy were enrolled, and received NucleomaxX, a dietary supplement with a high bioavailability of uridine (36 g TID every other day for 16 weeks). Patients were then followed off-uridine for another 16 weeks. Highly active antiretroviral therapy remained unchanged during the trial.Results-Fourteen patients completed the study. Two subjects dropped out before week 4 for study-unrelated reasons. No adverse events were noted throughout the study. HIV-1 RNA, CD4 counts, liver enzymes and hemoglobin remained unchanged. Body mass index, lactate, lipids, insulin and homeostasis model assessment of insulin resistance were unaltered. Fat and peripheral blood and mononuclear cell mtDNA levels did not correlate with each other and exhibited no changes throughout the study. Lipoatrophy scores by patients and physician improved significantly at weeks 16 and 32 compared to study entry.Conclusion-In this pilot study, NucleomaxX was safe, well tolerated without apparent deleterious effect on HIV indices. In contrast to in vitro data, NucleomaxX did not lead to changes in fat or blood mtDNA levels.

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Evidence of Nucleoside Analogue Reverse Transcriptase Inhibitor–Associated Genetic and Structural Defects of Mitochondria in Adipose Tissue of HIV-Infected Patients

Cited by 60 publications

References 20 publications

Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine

Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine

Polymorphisms inFasGene Is Associated with HIV-Related Lipoatrophy in Thai Patients

Uridine supplementation in HIV lipoatrophy: pilot trial on safety and effect on mitochondrial indices

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