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1/2. Mitochondrial disruption and apoptosis in lymphocytes of an hiv infected patient affected by lactic acidosis after treatment with highly active antiretroviral therapy.

    AIMS: Highly active antiretroviral therapy (HAART) can induce an increase in lactic acid concentrations that seems to be caused by mitochondrial dysfunction induced by the interaction of nucleoside reverse transcriptase inhibitors (NRTIs) with DNA polymerase gamma in the mitochondria. Mitochondrial alterations have been described in liver and muscle cells of NRTI treated human immunodeficiency virus (hiv) infected patients. Because lymphocytes are the main target for hiv and because mitochondria are involved in apoptosis, we studied mitochondrial morphology and apoptosis in the lymphocytes of an hiv infected patient with severe lactic acidosis after treatment with stavudine, didanosine, and indinavir. methods: The patient was a 39 year old woman. After two years of treatment she developed rapid weight loss with severe fat wasting, peripheral neuropathy, and hyperlacticaemia, which persisted after treatment withdrawal. The numbers and the morphology of the mitochondria were evaluated by electronic microscopy; the percentage of apoptotic cells was calculated by flow cytometry after staining with annexine V and by fluorescent microscopy after staining with ethidium bromide and acridine orange. RESULTS: The numbers of mitochondria in the lymphocytes were greatly decreased when compared with the lymphocytes of healthy individuals. The most important mitochondrial morphological alterations were swelling and the disruption of cristae and internal mitochondrial structure. These alterations were more evident during the period in which lactic acid values were very high. Moreover, a high percentage of apoptotic lymphocytes was seen. Morphological examination conducted one week after the normalisation of lacticaemia showed a pronounced increase in the number of mitochondria. The morphological alterations were no longer evident, although the size of each mitochondrion was smaller than normal. Moreover, the percentage of apoptotic cells was lower than 5%. CONCLUSIONS: This report describes important morphological alterations in lymphocyte mitochondria in an hiv infected patient during a severe phase of HAART induced hyperlacticaemia. These alterations persisted for several weeks after treatment withdrawal and were associated with an increase in lymphocyte apoptosis. Considering the important role of mitochondria in the apoptotic pathway, the increase in lymphocyte apoptosis may be a consequence of proapoptotic factors released from altered mitochondria.
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ranking = 1
keywords = apoptosis
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2/2. Tubular cell apoptosis and cidofovir-induced acute renal failure.

    Cidofovir is an antiviral drug with activity against a wide array of dna viruses including poxvirus. The therapeutic use of cidofovir is marred by a dose-limiting side effect, nephrotoxicity, leading to proximal tubular cell injury and acute renal failure. Treatment with cidofovir requires the routine use of prophylactic measures. A correct knowledge of the cellular and molecular mechanisms of cidofovir toxicity may lead to the development of alternative prophylactic strategies. We recently cared for a patient with irreversible acute renal failure due to cidofovir. Renal biopsy showed tubular cell apoptosis. Cidofovir induced apoptosis in primary cultures of human proximal tubular cells in a temporal (peak apoptosis at 7 days) and concentration (10-40 microg/ml) pattern consistent with that of clinical toxicity. apoptosis was identified by the presence of hypodiploid cells, by the exposure of annexin V binding sites and by morphological features and was associated with the appearance of active caspase-3 fragments. cell death was specific as it was also present in a human proximal tubular epithelial cell line (HK-2), but not in a human kidney fibroblast cell line, and was prevented by probenecid. An inhibitor of caspase-3 (DEVD) prevented cidofovir apoptosis. The survival factors present in serum, insulin-like growth factor-1 and hepatocyte growth factor, were also protective. The present data suggest that apoptosis induction is a mechanism contributing to cidofovir nephrotoxicity. The prophylactic administration of factors with survival activity for tubular epithelium should be further explored in cidofovir renal injury.
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ranking = 1.125
keywords = apoptosis
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