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doi: 10.1177/135965350501002s02pmid: N/A
In recent years, research into nucleoside reverse transcriptase inhibitor (NRTI)-related mitochondrial (mt) toxicity in HIV therapy has led to conflicting results and many unanswered questions regarding the molecular mechanisms that lead to such toxicity. From the early hypothesis that inhibition of the human mt polymerase γ by NRTIs was responsible for the drugs’ mt toxicity, an increasingly complex picture is emerging that probably involves multiple mt pathways. Results have been presented suggesting that NRTIs affect not only mtDNA but also mtRNA, nucleotide phosphorylation and the mt respiratory chain. Based on the current level of knowledge, this overview addresses some of the potential mechanisms through which NRTIs could affect mitochondria and ultimately cause the toxicity symptoms observed in HIV patients receiving NRTI-containing antiretroviral therapy.
Matarrese, Paola; Tinari, Antonella; Gambardella, Lucrezia; Mormone, Elisabetta; Narilli, Piero; Pierdominici, Marina; Cauda, Roberto; Malorni, Walter
doi: 10.1177/135965350501002s04pmid: N/A
It has been demonstrated that HIV protease inhibitors (PIs) are able to inhibit apoptosis of both infected and uninfected T cells. It was hypothesized that the mechanisms underlying this effect are associated with a specific activity of these drugs against mitochondrial modifications occurring in the execution phase of apoptosis. In this work, we investigated the activity of PIs towards the early changes occurring in mitochondrial membrane potential in freshly isolated uninfected human T lymphocytes sensitized to CD95/Fas-induced physiological apoptosis via pre-exposure to HIV envelope protein gp120. The results obtained clearly indicate that PIs are capable of hindering early morphogenetic changes bolstering T cell apoptosis, that is, cell polarization and mitochondrial hyperpolarization. The target effect on mitochondria appeared to be characterized by a specific activity of PIs in the maintenance of their homeostasis either in intact cells or in cell-free systems, that is, isolated mitochondria. PIs seem to act as boosters of mitochondrial defense mechanisms, including modulation of endogenous uncouplers. These results add new insights in the field of PI mitochondrial toxicity mechanisms and pharmacological perspectives for the use of these drugs in the control of immune system homeostasis.
Miró, Òscar; López, Sònia; Cardellach, Francesc; Casademont, Jordi
doi: 10.1177/135965350501002s08pmid: N/A
Chronic use of antiretrovirals (ARVs) to treat HIV infection, along with more prolonged patient survival, has been associated with an increase in adverse drug effects in HIV-infected patients on treatment. It has been proposed that some of these adverse effects (including myopathy, cardiomyopathy, anaemia, hyperlactataemia/ lactic acidosis, pancreatitis, polyneuritis and lipodystrophy) could be mediated by mitochondrial (mt) toxicity. From the experimental data, it has been proposed that nucleoside analogue reverse transcriptase inhibitors (NRTIs) also inhibit γ-polymerase, the enzyme devoted to replicate (and, to a lesser extent, repair) mtDNA. It is now widely accepted that the use of most NRTIs in HIV-infected patients is associated with mtDNA depletion. Although cross-sectional studies suggest that certain ARVs, especially stavudine, are more toxic to mitochondria, the differences among different highly active ARV therapy (HAART) schedules detected in the analysis of longitudinal studies are not so clear. These types of study in previously untreated individuals suggest that the greatest mtDNA loss appears at the beginning of the treatment. Conversely, in ARV-experienced patients, the potential beneficial effects of HAART changes in terms of mtDNA content remain controversial and must be further investigated. Functional studies accompanying genetic investigations are needed for the correct pathogenic interpretation of the mtDNA abnormalities.
Gerschenson, Mariana; Shiramizu, Bruce; LiButti, Daniel E; Shikuma, Cecilia M
doi: 10.1177/135965350501002s09pmid: N/A
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 realtime 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.
Mallon, Patrick WG; Sedwell, Rebecca; Unemori, Patrick; Kelleher, Anthony; Cooper, David A; Carr, Andrew
doi: 10.1177/135965350501002s11pmid: N/A
In the majority of cases, HIV-associated lipodystrophy, lipoatrophy in particular, becomes clinically apparent only after months or years of continuous exposure to antiretroviral medications and, once developed, is difficult to reverse. Many lipid-related side effects of antiretroviral medications result from drug-induced changes in gene expression. As our understanding of the pathogenic mechanisms underlying HIV-associated lipodystrophy improves, it is important to be able to explore changes at a molecular level in order to fully elucidate the mechanisms whereby antiretroviral drugs exert their toxicities. Monitoring changes in gene expression in vivo may enable physicians to identify, predict or prevent drug toxicities early, before irreversible changes in body composition occur. However, monitoring changes in gene expression at a population level presents many methodological challenges that need to be addressed, over and above the considerable intra- and inter-individual variability inherent in the cellular expression of any gene. Careful collection and processing of adequate biological samples, robust laboratory processes and assays, and appropriate study design can help overcome many of these difficulties.
de Mendoza, Carmen; Soriano, Vincent
doi: 10.1177/135965350501002s12pmid: N/A
Oxidative stress accompanying hepatitis C virus (HCV) infection seems to result in mitochondrial (mt) dysfunction. In HIV/HCV-coinfected individuals, HCV-related mt damage could be further enhanced and clinical manifestations of mt damage may appear, particularly following exposure to some antiretroviral drugs. Furthermore, when HCV medications are used together with certain antiretrovirals, the risk of developing mt adverse events may be particularly frequent, such as development of pancreatitis when ribavirin and didanosine are coadministered. The management of HIV/HCV-coinfected individuals needs to consider the high risk of mitochondria-associated toxicities in this population, which may significantly influence treatment decisions and therapeutic modalities.
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