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Biomedical subjects

Mariana Gerschenson

Publications and source records attributed to Mariana Gerschenson.

11 recordsLinked to original sources
PubMed2005

HIV-associated wasting in the era of highly active antiretroviral therapy: a syndrome of residual HIV infection in monocytes and macrophages?

Human immunodeficiency virus (HIV) infection in peripheral blood mononuclear cells (PBMCs) might be influencing the development of wasting in the era of potent antiretroviral therapy. In a retrospective study of 57 subjects, HIV proviral DNA levels in PBMCs were higher in subjects whose body weight decreased by >5% one year after initiation of highly active antiretroviral therapy, compared with subjects whose body weight was stable or increased (median HIV proviral DNA load, 8.9 vs. 0.9 copies/10(6) PBMCs; P = .006).

Adult↗
PubMed2005

Mitochondrial DNA levels of peripheral blood mononuclear cells and subcutaneous adipose tissue from thigh, fat and abdomen of HIV-1 seropositive and negative individuals.

Mitochondrial dysfunction has been demonstrated in subcutaneous adipose tissue from lipoatrophic HIV-1-infected patients treated with nucleoside reverse transcriptase inhibitors (NRTIs). To further assess mitochondrial toxicity, mitochondrial DNA (mtDNA) copies/cell were measured in subcutaneous fat from various sites. Peripheral adipose tissues were obtained from the abdominal wall near the umbilicus, anterior lateral thigh, and dorsal cervical region of the neck of individuals from four cohorts: 1) seven lipoatrophic HIV-1-infected patients receiving a regimen with nucleoside reverse transcriptase inhibitors (NRTIs) as part of highly active antiretroviral therapy (HAART) for > 6 months; 2) seven non-lipoatrophic HIV-1-infected patients receiving NRTIs-containing HAART; 3) five HIV-1-infected patients on antiretroviral therapy < 2 weeks (naive); 4) and five HIV-1-negative participants. Along with the adipose tissue samples, peripheral blood mononuclear cells (PBMC) were also obtained from each patient for mtDNA depletion examination. Total DNA was isolated and mtDNA copies/cell quantitated by competitive and real-time PCR. MtDNA copies/cell in abdomen, thigh, and neck fat were depleted in lipoatrophic HIV-1 seropositive compared to the seropositive naive and seronegative cohorts. MtDNA copies/cell in thigh and neck fat were also decreased in non-lipoatrophic subjects exposed to NRTIs compared with NRTI-naive and HIV seronegative controls. PBMC values did not differ among the cohorts and there was no correlation with lipoatrophy state or HIV-1 serostatus. Additionally, differences in mtDNA copies/cell were observed in the fat depots from seronegative subjects. Thigh fat mtDNA levels were 45-55% lower than abdomen and neck. These studies help demonstrate that mtDNA levels can vary in different subcutaneous adipose depots suggesting possible metabolic differences.

Adipose Tissue↗
PubMed2004

Mitochondrial dysfunction in AIDS and its treatment.

Advances in anti-retroviral therapy (ART) has led to improved survival of patients infected with the human immunodeficiency virus (HIV). ART for HIV patients is composed of a combination of nucleoside reverse transcriptase inhibitors (NRTI) and/or a non-nucleoside reverse transcriptase inhibitor (NNRTI), and/or a protease inhibitor (PI). The long-term exposure to ART and HIV are causing mitochondrial toxicities, such as myopathies, neuropathy, myelopoiesis, pancreatitis, lactic acidosis, hepatic steatosis, and lipodystrophy. The mitochondrial pathogenesis has been believed to be due exclusively to NRTI-induced inhibition of DNA polymerase-gamma; it is now apparent that the etiology is far more complex, involving multiple mechanisms as well as an effect by HIV per se. Current therapy for patients includes interruption or change in medications and mitochondrial co-factors.

Journal Article↗
PubMed2004

HIV-associated mitochondrial toxicity in pregnancy.

Pregnancy is associated with a variety of physiologic and metabolic changes designed to support the fetoplacental unit. In the presence of maternal human immunodeficiency virus (HIV) infection, the use of combination antiretroviral therapy including the nucleoside analog reverse transcriptase inhibitor (NRTI) zidovudine to prevent perinatal HIV transmission, has resulted in a dramatic decrease in perinatally acquired HIV. Human and animal studies during pregnancy report a possible association between NRTI containing antiretroviral regimens and mitochondrial toxicity in the newborn and mother. However, the possible long-term consequences on the fetus and mother of these NRTI containing regimens during pregnancy are largely unknown. This review will examine the data available on NRTI-induced mitochondrial toxicity associated with combination antiretroviral regimens used to prevent perinatal HIV transmission.

Journal Article↗
PubMed2004

Mitochondrial injury in the pathogenesis of antiretroviral-induced hepatic steatosis and lactic acidemia.

Antiretroviral medications have significantly improved the prognosis of individuals infected with the human immunodeficiency virus (HIV) by maintaining immune integrity and limiting the impact of opportunistic infections. However, these benefits have not come without a price as long-term complications of therapy are increasingly recognized as significant causes of morbidity and mortality. Many of these complications are thought to be mediated through mitochondrial injury, which appears to be the result of nucleoside analogue toxicity. A syndrome of fatty liver (steatosis) with lactic acidosis represents the most fulminant presentation of such antiretroviral toxicity, though milder variants of hepatic steatosis with or without lactate elevations have also been described in HIV-seropositive individuals. The spectrum of hepatic steatosis and hyperlactatemia is likely multifactorial and may share some features with non-alcoholic fatty liver disease (NAFLD), which is the hepatic component of the metabolic syndrome described in the general population. As antiretrovirals are also known to contribute to metabolic syndrome components including insulin resistance, hypertriglyceridemia, and central adiposity, the possibility of common pathophysiologic mechanisms underlying NAFLD and antiretroviral-associated fatty liver seem likely. However, lactate elevations are not a component of NAFLD, suggesting other factors must also be involved. A review follows which details the role of mitochondrial damage in hepatic steatosis among HIV-infected individuals and the general population, as well as the association of this damage to the pathogenesis of hyperlactatemia.

Journal Article↗
PubMed2004

Mitochondrial toxicity in fetal Erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine.

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.

Animals↗
PubMed2004

Acetyl-L-carnitine for the treatment of HIV lipoatrophy.

Lipodystrophy is an increasingly recognized complication of antiretroviral therapy for human immunodeficiency virus (HIV) infection. This syndrome encompasses both fat accumulation and wasting, which may be accompanied by metabolic derangements in glucose and lipid metabolism. While the precise mechanism of its development is not fully understood, lipodystrophy may represent chronic mitochondrial toxicity due to antiretroviral therapy and/or chronic HIV infection. Treatment of this condition has proven difficult, prompting research into agents that promote fat metabolism and mitochondrial function. L-carnitine is a nonessential micronutrient that regulates fatty acid transport into the mitochondrial matrix for metabolism via beta-oxidation. HIV-infected individuals on antiretroviral therapy may become deficient in this cofactor, limiting mitochondrial fat metabolism. While studies have shown some benefit for carnitine supplementation in cardiovascular disease, mitochondrial myopathies, and possibly male infertility, the data for its use in HIV-infected individuals are limited. Given its known physiologic function and the hypothesized mitochondrial basis for lipodystrophy, carnitine supplementation for this antiretroviral toxicity is reviewed. The available data from several small studies are inconclusive, although further research into this promising agent is warranted.

Acetylcarnitine↗
PubMed2003

Placenta and cord blood mitochondrial DNA toxicity in HIV-infected women receiving nucleoside reverse transcriptase inhibitors during pregnancy.

Recent studies of pregnant women and animal models have raised concerns regarding potentially serious mitochondrial toxicity-related side effects in infants born to mothers who received nucleoside reverse transcriptase inhibitors (NRTIs) during their pregnancy to prevent HIV-1 perinatal transmission. The aim of this study was to assess mitochondrial DNA (mtDNA) content of cord blood and placenta in HIV-infected pregnant women receiving NRTI compared with HIV-negative women, hypothesizing that placenta and cord blood mtDNA copies per cell would be decreased in women on NRTI therapy. Immediately following delivery, placenta and cord blood were obtained from eight HIV-infected pregnant women on NRTIs and five HIV-negative women. Assessment of mtDNA copies per cell was accomplished by quantitative real-time PCR. The mean mtDNA copies per cell from the placenta of the HIV-infected women compared with HIV-negative women was 152 +/- 119 and 880 +/- 136 ( =.0016), respectively. Similarly, the mean mtDNA copies per cell from the cord blood of the HIV-positive women compared with HIV-negative women was 144 +/- 101 and 865 +/- 331 ( =.0026), respectively. There was a statistically significant decrease in mtDNA copies per cell in placenta and cord blood between the HIV-infected women on NRTIs compared with HIV-negative women. Further studies are needed to better understand the morbidity to infants and mothers treated with NRTI to prevent vertical transmission of HIV.

Base Sequence↗
PubMed2002

Mitochondrial dysfunction and antiretroviral nucleoside analog toxicities: what is the evidence?

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.

Journal Article↗