Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent advances in the development of three different types of antiviral drugs, the nucleotide and non-nucleotide analogues acting as reverse transcriptase inhibitors (NRTIs) and the nonpeptidic viral protease inhibitors (PI), and their introduction in the management of patients with AIDS, either alone or in combination, have dramatically improved the clinical course of the disease and prolonged life expectancy in patients with AIDS. The increase in life expectancy in association with the long-term use of the above antiviral agents, however, have generated novel morbidities and complications. Central among them is the quite common AIDS-related insulin resistance and lipodystrophy syndrome, which is characterized by a striking phenotype and marked metabolic disturbances. To look for the pathologic causes of this particular syndrome, we focused on one of the HIV-1 accessory proteins, Vpr, which has multiple functions, such as virion incorporation, nuclear translocation of the HIV-1 preintegration complex, nucleo-cytoplasmic shuttling, transcriptional activation, and induction of apoptosis. Vpr may also act like a hormone, which is secreted into the extracellular space and affects the function of distant organs. Vpr functions as a coactivator of the glucocorticoid receptor and potentiates the action of glucocorticoid hormones, thereby inducing tissue glucocorticoid hypersensitivity. Vpr also arrests host cells at the G2/M phase of the cell cycle by interacting with novel 14-3-3 proteins. Vpr facilitates the interaction of 14-3-3 and its partner protein Cdc25C, which is critical for the transition of G2/M checkpoint in the cell cycle, and suppresses its activity by segregating it into the cytoplasm. The same Vpr protein also suppresses the association of 14-3-3 with other partner molecules, the Foxo transcription factors. Since the Foxo proteins function as negative transcription factors for insulin, Vpr may cause resistance of tissues to insulin. Through these two newly identified functions of Vpr, namely, coactivation of glucocorticoid receptor activity and inhibition of insulin effects on Foxo proteins, Vpr may participate in the development of AIDS-related insulin resistance/lipodystrophy syndrome.
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PMID:Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/lipodystrophy syndrome? 1526 80

HIV-positive persons requiring a highly active antiretroviral therapy containing one or more nucleosidic reverse transcriptase inhibitors associated with or without protease inhibitors are exposed to metabolic side effects among which lipodystrophy and hyperlactemia, defined by blood lactates higher than 2,25 mmol/L. Hyperlactatemia had to be differentiated from lactic acidosis of type B (without hypoxemia, lactates higher than 5 mmol/L and arterial pH lower than 7,3), a rare but potentially fatal complication by multi-visceral failure. The accused INRT induce mitochondrial toxicity by inhibition of DNA gamma polymerase and deterioration of its DNA. Our exploratory study, troop of 282 patients, identified age and stavudine like statistically associated, which has occurred of this metabolic anomaly. The patients having profited of a therapeutic change with the profit from drugs minus hyperlactatogenic presented an obvious clinical and biological improvement; whereas similar switch of therapy occurred for the lipodystrophic patients presented any clinical improvement. Nevertheless, biological parameters (blood lactates, triglycerides, total cholesterol and LDL-cholesterol) were significantly decreased after this therapeutic switch occurred on the lipodystrophic patients. In conclusion, the measurement of the following biological parameters: glycemia, lactatemia, triglycerides, total cholesterol and LDL-cholesterol at patient VIH, in a simple and rigorous pre-analytical and analytical context, appears to us justified in the monitoring of metabolic disorders in treated HIV patients by INRT and/or IP.
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PMID:[Outcome of hyperlactatemia and lipodystrophy syndromes in patients infected with human immunodeficiency virus]. 1529 45

HIV-infected subjects who have lipodystrophy and insulin resistance on prolonged antiretroviral therapy have elevated levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) antigens, markers of impaired thrombolysis that are associated with hyperinsulinemia and increased cardiovascular risk. We studied HIV-infected, protease inhibitor (PI)-naive adults treated with indinavir (n = 11) or amprenavir (n = 14) plus two nucleoside reverse transcriptase inhibitors enrolled in two independent prospective trials. Antiretroviral and immune responses were similar in both studies. Over 8 wk, indinavir was associated with decreased insulin sensitivity, whereas amprenavir was not. Levels of tPA antigen declined by approx 25% with both treatments (p < 0.05 for each); levels of PAI-1 antigen did not change. Levels of the inflammatory marker soluble tumor necrosis factor-alpha receptor II (sTNFr2) correlated positively with tPA antigen (r = 0.33, p = 0.02), and mean (SD) plasma concentrations of sTNFr also declined with treatment (4.44 +/- 1.11 ng/mL pretherapy, 3.75 +/- 1.21 posttherapy, p = 0.007). Short-term improvement in a marker of impaired thrombolysis and increased vascular risk can occur during PI-based antiretroviral therapy, perhaps as a consequence of improvement in HIV-related inflammation. This improvement occurred independent of development of insulin resistance, which occurred only with indinavir.
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PMID:Changes in thrombolytic and inflammatory markers after initiation of indinavir- or amprenavir-based antiretroviral therapy. 1537 33

Each of the 3 traditional classes of antiretroviral drugs (nucleoside/nucleotide reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors [PIs]) has characteristic sets of toxicities that are not found with the other drug classes. On the other hand, lipodystrophy, which was thought to be specific to PIs, is now known to be common to all 3 classes of drugs. An understanding of the drug-specific, class-specific, and general toxicities and side effects of antiretroviral drugs will help the clinician tailor treatment regimens to individual patients.
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PMID:Recognizing and managing common toxicities in patients receiving antiretroviral therapy. 1549 18

(1) First-line antiretroviral combinations generally include, in addition to a protease inhibitor or a non nucleoside reverse transcriptase inhibitor, two nucleoside reverse transcriptase inhibitors, namely zidovudine + didanosine, stavudine + lamivudine, or zidovudine + lamivudine. (2) Tenofovir disoproxil (referred to simply as tenofovir below) is a nucleotide HIV reverse transcriptase inhibitor. Previously recommended for second-line treatment in case of virological failure, it is now approved for first-line therapy in adults. (3) This licence extension is based on a double-blind trial comparing tenofovir + lamivudine + efavirenz with stavudine + lamivudine + efavirenz in 602 patients. After 96 weeks, three-quarters of patients had undetectable viral load (<50 copies/ml), and there was no statistically significant difference among the groups. (4) The number of serious adverse effects was similar in the two groups. Relative to the stavudine combinations, there were fewer reports of lipodystrophy (1% versus 12%), fewer peripheral neuropathies (3% versus 10%) and fewer prescriptions of lipid-lowering therapy (2% versus 10%) among patients taking tenofovir. Tenofovir seemed to have a worse effect on renal function and bone metabolism, however. (5) Tenofovir is taken only once a day, but so are didanosine and lamivudine. (6) In practice, there is not yet enough evidence to support the routine use of tenofovir in first-line antiretroviral combinations. Tenofovir is, however, an interesting alternative when stavudine is poorly tolerated.
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PMID:Tenofovir: new indication. For first-line antiretroviral therapy: wait and see. 1549 99

The lipodystrophy syndrome and associated metabolic alterations are the most prevalent adverse effects in HIV-infected patients taking highly active anti-retroviral therapy (HAART). This syndrome involves profound disturbances in adipose tissue. The toxic effect of nucleoside reverse transcriptase inhibitors on mitochondrial function is a major contributor to the lipodystrophy syndrome. Although adipocytes were not expected to be preferential targets of mitochondrial toxicity, recent re-evaluation of the role of mitochondria in white adipocytes helps to explain the molecular basis of HAART-associated lipodystrophy. Adipocytes are a source of paracrine and endocrine signals that influence adipocyte biology and systemic metabolism. Mitochondrial disturbances elicited by HAART result in an abnormal perception of the bioenergetic status by adipocytes, thus leading to enhancement of catalytic pathways and apoptosis in peripheral adipose tissue, alterations in the differentiation of brown versus white adipocytes, and the release of hormonal signals that lead to systemic metabolic disturbances.
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PMID:Lipodystrophy associated with highly active anti-retroviral therapy for HIV infection: the adipocyte as a target of anti-retroviral-induced mitochondrial toxicity. 1568 Oct 26

Highly active antiretroviral therapy (HAART) has changed the natural history of HIV infection, but the presence of adverse events may limit its efficacy. Nucleoside reverse transcriptase inhibitors can cause mitochondrial toxicity and anemia, non-nucleoside reverse transcriptase inhibitors are associated with rash and central nervous system disturbance; protease inhibitors elicit gastrointestinal adverse effects and metabolic abnormalities including lipodystrophy syndrome, hyperlipidemia and insulin resistance. These complications have the potential to increase morbidity and mortality significantly in those requiring long-term treatment of HIV-infection. The presence of such abnormalities also has an impact on adherence to treatment. Besides providing health benefits, HAART may have a negative impact on patients' quality of life. Identifying and treating these complications has important implications for patient survival.
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PMID:[Side effects of antiretroviral therapy]. 1568 51

HIV-1-infected patients on antiretroviral therapy frequently develop a lipodystrophy syndrome, characterized by peripheral lipoatrophy and visceral fat redistribution associated with metabolic alterations including dyslipidemia and insulin resistance. Its pathophysiology remains unclear but the antiretroviral treatment, associating protease inhibitors (PIs) and nucleoside analogue inhibitors of the viral reverse transcriptase (NRTIs), plays a major role. Some antiretroviral molecules inhibit differentiation and induce insulin resistance and apoptosis in adipose cells both in vitro and in vivo. In vitro, PIs and NRTIs increase the expression and secretion of pro-inflammatory cytokines such as TNF alpha, IL-6 and L-1beta, which are involved in altered adipocyte functions and decrease that of adiponectin, a positive modulator of insulin sensitivity. Similar alterations are observed in fat and serum from HIV-1-infected lipodystrophic patients under antiviral treatment associating PIs and NRTIs. Altered adipokine secretion could result from patients' exposure to PIs and NRTIs and lead to altered adipocyte differentiation, insulin resistance and apoptosis, ultimately resulting in lipoatrophy. These disorders probably result in a decreased secretion of adiponectin and an increased release of free fatty acids by insulin-resistant adipose tissue. Therefore, they could be involved in whole body insulin resistance and metabolic alterations in lipodystrophic HIV-1-infected patients.
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PMID:HIV antiretroviral treatment alters adipokine expression and insulin sensitivity of adipose tissue in vitro and in vivo. 1573 39

Nucleoside reverse transcriptase inhibitor (NRTI) treatment of HIV is associated with complications, including lipodystrophy (LD) and myopathy. Inhibition of mitochondrial DNA polymerase and depletion of mtDNA by NRTI triphosphates are believed to be key mechanisms in NRTI toxicity. Here, we determined the activities and mRNA levels of deoxynucleoside kinases (dNK) and 5'-nucleotidases (5'-NT) controlling the rate-limiting step in intracellular phosphorylation of NRTIs in cell models representing adipose, muscle tissue and peripheral blood cells using specific assays and Taqman RT-PCR. In vitro phosphorylation of 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-didehydro-2',3'-dideoxythymidine (d4T) in extracts was also determined. 3T3-L1 adipocytes showed similar activity of mitochondrial thymidine kinase-2 (TK2) and deoxyguanosine kinase (dGK) but 3- to 36-fold lower levels of cytosolic deoxycytidine kinase (dCK), thymidine kinase-1 (TK1) and thymidine monophosphate kinase (TMPK) and higher levels of deoxyribonucleotidase activity compared to proliferating 3T3-L1. dCK, dGK and TK2 activities correlated with their mRNA levels in proliferating, resting and differentiating 3T3-L1. Differentiated L6 myoblasts had lower activities of cytosolic dNK's and TMPK, higher dGK and similar TK2 and deoxyribonucleotidases (dNT) activities compared to proliferating myoblasts. TK2 was the limiting dNK activity while dGK was predominant in adipocytes and myocytes. Activity profiles revealed limited capacity to phosphorylate dThd and dCyd in adipocytes and myocytes compared to proliferating cells and CEM lymphocytes. Phosphorylation of AZT and d4T was low in adipocytes and myocytes, and the presence of these analogs inhibited the phosphorylation of dThd by TK2 suggesting that mitochondrial toxicity of some NRTIs in adipocytes and myocytes is due to the depletion of normal mitochondrial dNTP pools.
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PMID:Activity profiles of deoxynucleoside kinases and 5'-nucleotidases in cultured adipocytes and myoblastic cells: insights into mitochondrial toxicity of nucleoside analogs. 1574 6

Therapeutic strategies for combating HIV-associated lipodystrophy, and lipoatrophy in particular, have been a major focus of HIV clinical research. The initial impetus focused on protease inhibitor withdrawal strategies, which resulted in improved lipid profiles and insulin resistance but no change in subcutaneous or visceral adipose tissue. Nucleoside reverse transcriptase inhibitor withdrawal strategies, specifically withdrawal of thymidine analogues, have achieved greater success in the reversal of lipoatrophy. In particular, the MITOX extension study demonstrated a 35% improvement in limb fat over a 2 year period after a switch from a thymidine analogue to abacavir. However, recovery from lipoatrophy is a slow process, and limited access to and potential toxicities introduced by alternative therapies can limit switch strategies. The use of thiazolidinediones as agents to reverse lipoatrophy has, unfortunately, been shown to be ineffective, as have alternative therapeutic approaches with agents such as metformin, lipid-lowering agents and growth hormones. Although prevention of lipodystrophy may be the only definitive approach to combat this syndrome, the role of intermittent highly active antiretroviral therapy as a means of reducing the incidence, or slowing the development, of lipodystrophy is currently under evaluation.
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PMID:Therapeutic approaches to combating lipoatrophy: do they work? 1576 Oct 72


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