In Vivo, Nucleoside Reverse-Transcriptase Inhibitors Alter Expression of Both Mitochondrial and Lipid Metabolism Genes in the Absence of Depletion of Mitochondrial DNA
ABSTRACT Nucleoside reverse-transcriptase inhibitors (NRTIs), which are used to treat human immunodeficiency virus (HIV) infection, can cause mitochondrial dysfunction and have been associated with lipoatrophy. The effects of this mitochondrial dysfunction on lipid metabolism, at a molecular level in vivo, have not been described.
We examined early changes (by 2 weeks after initiation of therapy) in expression of mitochondrial and nuclear genes in adipose tissue from 20 HIV-negative subjects randomized to receive dual-NRTI therapy (zidovudine/lamivudine or stavudine/lamivudine) for 6 weeks.
We observed decreased transcription of mitochondrial (mt) RNA without significant depletion of mtDNA. Decreases in mtRNA coincided with simultaneous up-regulation of nuclear genes involved in transcriptional regulation of mtRNA (NRF1 and TFAM) and oxidation of fatty acids (PPARA and LPL), whereas PPARG, which is important for differentiation of adipose tissue, was down-regulated. Many nuclear changes correlated with changes in peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC1), suggesting a central role for PGC1 in nuclear responses to mitochondrial dysfunction. Expression of peripheral blood monocyte mtRNA also decreased, suggesting that monocytes may be surrogates for NRTI-induced mitochondrial dysfunction in other tissues.
Independent of HIV, NRTIs decrease transcription of mtRNA in vivo. The absence of depletion of mtDNA suggests that NRTIs cause mitochondrial dysfunction by means other than through inhibition of DNA polymerase- gamma , whereas disruption of expression of lipid metabolism genes offers an explanation for NRTI-induced lipoatrophy.
- SourceAvailable from: Jose A. Oteo
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- "A study has demonstrated increased plasma mtDNA in acute HIV seroconverters and ART-naive subjects compared with HIV-seronegative controls and long-term nonprogressors, and a positive correlation between plasma HIV RNA and plasma mtDNA was also observed . However, it is worth mentioning that both increases and decreases in mtDNA have been reported in pathogenic conditions as there is not a standard tool for defining what constitutes an abnormal mtDNA quantity, and therefore, data from heterogeneous HIV-infected populations were inconsistent     . "
ABSTRACT: Highly active antiretroviral therapy (HAART) has considerably improved the prognosis of HIV-infected patients. However, prolonged use of HAART has been related to long-term adverse events that can compromise patient health such as HIV-associated lipodystrophy syndrome (HALS) and nonalcoholic fatty liver disease (NAFLD). There is consistent evidence for a central role of mitochondrial dysfunction in these pathologies. Nucleotide reverse transcriptase inhibitors (NRTIs) have been described to be mainly responsible for mitochondrial dysfunction in adipose tissue and liver although nonnucleoside transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) have also showed mitochondrial toxicity, which is a major concern for the selection and the long-term adherence to a particular therapy. Several mechanisms explain these deleterious effects of HAART on mitochondria, and evidence points to other mechanisms beyond the "Pol- γ hypothesis." HIV infection has also direct effects on mitochondria. In addition to the negative effects described for HIV itself and/or HAART on mitochondria, HIV-infected patients are more prone to develop a premature aging and, therefore, to present an increased oxidative state that could lead to the development of these metabolic disturbances observed in HIV-infected patients.Oxidative Medicine and Cellular Longevity 07/2013; 2013:493413. DOI:10.1155/2013/493413 · 3.36 Impact Factor
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- "Numerous mechanisms have been proposed to explain the deleterious impact of NRTIs including mitochondrial depletion, impaired mitochondrial replication via inhibition of the mitochondrial DNA polymerase gamma (POLγ), and subsequent increase in reactive oxygen species (ROS; Lewis et al. 2003). POLγ-independent mechanisms of impairing mitochondrial function have also been implicated, including decreased mitochondrial DNA transcription and altered expression of lipid metabolism genes (Mallon et al. 2005). Mitochondrial dysfunction is a feature of a number of neurodegenerative diseases including AD, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease (Knott et al. 2008; Lin and Beal 2006). "
ABSTRACT: The human immunodeficiency virus (HIV) invades the central nervous system early in the course of infection and establishes a protected viral reservoir. However, neurocognitive consequences of HIV infection, known collectively as HIV-associated neurocognitive disorders (HAND), develop in only a small portion of infected patients. The precise mechanisms of pathogenesis involved in HIV-induced central nervous system injury are still not completely understood. In particular, most theories of HAND pathogenesis cannot account for either the selective vulnerability of specific neuronal populations to HIV-induced neurodegeneration or why only a subset of patients develop clinically detectable nervous system disease. Epidemiological and virological studies have identified a variety of host and viral factors that are associated with increased risk of developing HAND. Some host factors that predispose HIV-infected patients to HAND overlap with those associated with Alzheimer's disease (AD), suggesting the possibility that common pathogenic mechanisms may participate in both diseases. Here, we will review reports of host and viral factors associated with HAND and place these studies in the context of the data employed to support current theories regarding the molecular and cellular mechanisms that lead to HIV-induced neurodegeneration with additional focus on mechanisms common to AD pathogenesis.Journal of Neuroimmune Pharmacology 05/2009; 4(2):175-89. DOI:10.1007/s11481-009-9154-6 · 3.17 Impact Factor
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- "On the other hand, there have been suggestions that antiretroviral treatment causes lipodystrophy only when acting upon HIV-1-infected patients, and that events related to HIV-1 infection are intrinsically associated with the development of the syndrome. Evidently, there are no data on long-term antiretroviral treatment of non-HIV-1- infected patients that could establish the specific role of HAART independent of the HIV-1 infection, and a single two-week study of nucleotide-analog reverse transcriptase inhibitor treatment of non-infected volunteers indicated the appearance of only a few features of the lipodystrophy syndrome . Some data have indicated that mild alterations of adipose tissue biology are already present in nontreated HIV-1- infected patients . "
ABSTRACT: PPARγ is a ligand-dependent master transcription factor controlling adipocyte differentiation as well as multiple biological processes taking place in other cells present in adipose tissue depots such as macrophages. Recent research indicates that HIV-1 infection-related events may alter adipose tissue biology through several mechanisms involving PPARγ, ranging from direct effects of HIV-1-encoded proteins on adipocytes to the promotion of a proinflammatory environment that interferes with PPARγ actions. This effect of HIV-1 on adipose tissue cells can occur even in the absence of direct infection of adipocytes, as soluble HIV-1-encoded proteins such as Vpr may enter cells and inhibit PPARγ action. Moreover, repression of PPARγ actions may relieve inhibitory pathways of HIV-1 gene transcription, thus enhancing HIV-1 effects in infected cells. HIV-1 infection-mediated interference of PPARγ-dependent pathways in adipocytes and other cells inside adipose depots such as macrophages is likely to create an altered local environment that, after antiretroviral treatment, leads to lipodystrophy in HIV-1-infected and HAART-treated patients.PPAR Research 02/2009; 2009:607902. DOI:10.1155/2009/607902 · 1.64 Impact Factor