Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.16 (HIV-1 protease)
 2,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HIV-1 protease inhibitors have contributed significantly to the reduction in morbidity and mortality associated with HIV-1 disease. Some of their clinical benefit may be attributed to inhibition of non-viral pathogen proteases and mammalian proteases involved in apoptosis. Our objective was to investigate the effect of HIV-1 protease inhibitors on two different mechanisms of apoptosis in cells not exposed to HIV-1. Modulation of apoptosis induced in U937 or Jurkat cells by CD95 (Fas-ligand) or TNF-alpha was measured using flow cytometry using the 7-AAD and annexin/propidium iodide methods. - HIV-1 protease inhibitors reduced TNF-alpha mediated cell death in a dose-dependent manner, with a maximum inhibition ranging between 38% and 60% observed for 100 microM indinavir. Saquinavir and ritonavir, but not nelfinavir also inhibited TNF-alpha induced cell death. Nevirapine (an HIV-1 reverse transcriptase inhibitor) showed no effect. The TNF-alpha activity was also inhibited by the caspase inhibitors Z-VAD-fmk at concentrations of 10 microM or less, and by DEVD-cmk. In contrast, HIV-1 protease inhibitors did not affect CD95 induced apoptosis in Jurkat cells at any of the concentrations tested. Our findings indicate that HIV-1 protease inhibitors may act on mammalian proteases involved in the regulation of apoptosis; whether this is relevant in the clinical setting remains to be established. Identification of the pathways involved may lead to a better understanding of the clinical impact of this drug class and their role in HAART associated toxicities.
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PMID:Inhibition of TNF-alpha mediated cell death by HIV-1 specific protease inhibitors. 1257 50

HIV-1 protease inhibitors (PIs) may improve hematopoietic functions owing to their direct effects on bone marrow (BM) progenitor cells. In this study we investigated this hypothesis evaluating the effect of adding ritonavir (RTV) and indinavir (IND) on hematopoietic colony formation assays by colony-forming cell (CFC) and long-term culture-initiating cell (LTC-IC) assays, on apoptosis, on cytokine production and stromal cells, in subjects with HIV-1 infection, and in seronegative controls. After PI addition, CFC and LTC-IC assays in HIV-1-infected patients showed levels of colony growth significantly higher than those observed at baseline; the same PI activity on colony formation was observed in healthy subjects. No significant modifications on Fas, the membrane form of Fas (mFas) and Fas-ligand (FasL) expression, and on cytokine production were observed at BM level after the addition of PIs. At baseline, in HIV-1-infected patients, the majority of the stromal cells appeared as large and rounded, whereas after the addition of RTV or IND the stromal cells exhibited a "fibroblast-like" morphology and produced higher stem cell factor (SCF) and lower MIP-1alpha levels when compared with the stromal production without the addition of IND. RTV and IND increased colony growth of BM obtained either from HIV-1-infected patients or from normal individuals, in parallel with the normalization of functional and morphological characteristics of stromal cells.
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PMID:HIV type 1 protease inhibitors enhance bone marrow progenitor cell activity in normal subjects and in HIV type 1-infected patients. 1566 44

Hematological abnormalities frequently occur in patients infected with HIV-1. Increasing evidence indicates that bone marrow (BM) suppression results from viral infection of accessory cells, with impaired stromal function and alteration of hematopoietic growth factor network. We investigated the effects of antiretroviral therapy on cytokine and chemokine production by BM cells and stromal cells, in a group of HIV-1-infected subjects before and during treatment. Compared with uninfected controls, an altered cytokine and chemokine production by BM cells has been observed before treatment, characterised by decreased IL-2 and elevated TNF-alpha, MIP-1alpha, MIP-1beta, and RANTES levels, along with a defective BM clonogenic activity. Antiretroviral therapy determined an amelioration of stem cell activity, a restoration of stromal cell pattern and functions, and an increased IL-2 production at BM level and a decrease of Fas expression on progenitor cells, in parallel with the diminution of TNF-alpha levels. HIV-1 protease inhibitors (PIs) may improve hematopoietic functions owing to their direct effects on the BM progenitor cells. Ritonavir and indinavir increased the colony growth of BM obtained either from HIV-1-infected patients or from normal individuals, in parallel with the normalization of functional and morphologic characteristics of stromal cells.
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PMID:Immunodysregulation of HIV disease at bone marrow level. 1621 83