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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have evaluated a possible role for human immunodeficiency virus type 1 protease during early steps of replication. For these studies, a specific inhibitor of human immunodeficiency virus protease, Ro31-8959, was used. Synthesis of viral cDNA, its integration into cellular DNA, and its transcription were determined during a one-step, acute infection of MT-4 cells. No consistent difference in any of these parameters was noted between control-infected cultures and those treated with protease inhibitor. However, no infectious progeny virus was produced in treated cultures, and thus spread of infection was severely restricted. Our results do not support an essential activity of viral protease in early steps of replication but are in line with its established role in gag and gag-pol processing and in maturation to infectious progeny virus.
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PMID:Progression of early steps of human immunodeficiency virus type 1 replication in the presence of an inhibitor of viral protease. 137 15

The processing of the human immunodeficiency virus (HIV) gag and gag-pol precursor proteins by the virus-encoded protease is an essential step in maturation of infectious virus particles. Like most retroviral proteases, the HIV protease belongs to the aspartyl-protease family and can be inhibited by specific inhibitors. Twenty-four synthetic peptides known to be inhibitors of human renin were tested for inhibition of HIV replication in tissue cultures. One of them, a synthetic peptide analogue, SR41476, which has been shown to be a specific inhibitor of purified recombinant HIV1 protease in vitro, totally blocked infection with different isolates including the HIV1 LAV prototype, the highly cytopathic Zairian isolate HIV1 NDK, and HIV2 ROD, both in primary blood lymphocytes (PBL) and in the lymphoid cell lines MT4 and CEM, for at least 3 weeks. It also significantly reduced virus replication in chronically infected CEM cells, without any effect on cell proliferation. Radioimmunoprecipitation assay revealed that the inhibitor blocked processing of polyprotein precursors p55 gag and p40 gag into a mature form of gag proteins, p25 and p18. Synthetic peptide analogue SR 41476, when added before infection, efficiently inhibited formation of HIV DNA provirus and successfully suppressed synthesis of HIV-specific proteins. These results imply that the HIV protease inhibitor not only inhibited virus maturation in the late phase of the HIV replication cycle, but also interfered in the early phase, before the provirus was formed. This mechanism of antiviral activity provides new possibilities and strategies for AIDS chemotherapy.
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PMID:Inhibition of HIV by an anti-HIV protease synthetic peptide blocks an early step of viral replication. 148 Aug 23

Human immunodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS). Encoded by the HIV genome are several precursor proteins that undergo proteolytic cleavage to yield functional proteins. The env precursor protein is cleaved by a cellular protease. The gag precursor protein of HIV (p55), however, is cleaved by a virally encoded aspartate protease (HIV Protease). Cleavage of p55 is required for viral maturation and infectivity. There are also several host cell aspartate proteases that serve important homeostatic functions. Cathepsins D and E are lysosomal aspartate proteases which are believed to play an important role in macrophage function, and it has been suggested that inhibition of these enzymes by an HIV protease inhibitor may exacerbate immunosuppression in AIDS patients. We have studied the effect of SK&F 107461 (a hydroxyethylene dipeptide isostere inhibitor of HIV protease), on various host defense functions of human monocytes. Pepstatin A (an inhibitor of most aspartate proteases) and leupeptin (an inhibitor of serine and cysteine proteases) were included as controls. Although less potent than the prototypic aspartate protease inhibitor pepstatin, SK&F 107461 inhibited partially purified cathepsin D in vitro. However, in cell-based assays, SK&F 107461 had no effect on the degradation of hemoglobin, antigen processing of the protein antigen streptokinase, or secretion of 17-kD IL-1 beta by monocytes at concentrations which inhibit maturation of intracellular virus in HIV infected monocytes. Furthermore, SK&F 107461 had no effect on constitutive candidacidal activity. In contrast, leupeptin and pepstatin A partially inhibited accessory cell function of monocytes in the proliferative response to the recall antigen streptokinase. In addition, leupeptin partially inhibited degradation of hemoglobin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of a human immunodeficiency virus protease inhibitor on human monocyte function. 149 45

Synthetic peptide analog inhibitors of human immunodeficiency virus type 1 (HIV-1) protease were used to study the effects of inhibition of polyprotein processing on the assembly, structure, and infectivity of virions released from a T-cell line chronically infected with HIV-1. Inhibition of proteolytic processing of both Pr55gag and Pr160gag-pol was observed in purified virions from infected T cells after treatment. Protease inhibition was evident by the accumulation of precursors and processing intermediates of Pr55gag and by corresponding decreases in mature protein products. Electron microscopy revealed that the majority of the virion particles released from inhibitor-treated cells after a 24-h treatment had an immature or aberrant capsid morphology. This morphological change correlated with the inhibition of polyprotein processing and a loss of infectivity. The infectivity of virion particles purified from these chronically infected cell cultures was assessed following treatment with the inhibitor for 1 to 3 days. Virions purified from cultures treated with inhibitor for 1 or 2 days demonstrated a 95- to 100-fold reduction in virus titers, and treatment for 3 days resulted in complete loss of detectable infectivity. The fact that virions from treated cultures were unable to establish infection over the 7- to 10-day incubation period in the titration experiments strongly suggests that particles produced by inhibitor-treated cells were unable to reactivate to an infectious form when they were purified away from exogenous protease inhibitor. Thus, a block of HIV-1 protease processing of viral polyproteins by specific inhibitors results in a potent antiviral effect characterized by the production of noninfectious virions with altered protein structures and immature morphologies.
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PMID:Human immunodeficiency virus type 1 protease inhibitors irreversibly block infectivity of purified virions from chronically infected cells. 151 Apr 24

The standard angiotensin I (Ang I) radioimmunoassay for renin activity determination is a useful clinical tool for the diagnosis of high renin levels in certain cases of hypertension. It depends upon the liberation of Ang I from human plasma angiotensinogen. We considered whether a commercially available synthetic tetradecapeptide (TDP), Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser, would produce authentic Ang I upon incubation with protease from human immunodeficiency virus type 1 (HIV-1). This peptide is also known to be cleaved by renin at the Leu-Leu bond to yield the decapeptide Ang I. When the TDP is incubated with the HIV-1 protease, the peptide is readily hydrolyzed. Product formation is linear with respect to time and enzyme concentration. HPLC analysis of reaction products showed two new peaks, as one would expect from the cleavage of a TDP into a decapeptide and a tetrapeptide. Amino acid analysis of HPLC-purified peaks confirmed that the HIV-1 protease cleaves TDP at the Leu10-Leu11 site to produce the desired decapeptide, Ang I. Production of Ang I by the HIV-1 protease, like human renin, is inhibited in the presence of a protease inhibitor. Implications of the discovery of an HIV-1 protease substrate that produces authentic Ang I are discussed in light of a screening assay for soluble HIV-1 protease inhibitors.
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PMID:Could angiotensin I be produced from a renin substrate by the HIV-1 protease? 179 23

The structural proteins of the retroviral capsid are translated as a polyprotein (the Gag precursor) that is cleaved by a virally encoded protease. Processing of the human immunodeficiency virus type 1 Gag precursor Pr55 was analyzed through a combination of pulse-chase labeling, cell fractionation, and immunoprecipitation. We observed a membrane-associated processing pathway for the Gag precursor that gives rise to virions. In addition, we found that a significant amount of processing occurs in the cytoplasm of infected cells resulting in the intracellular accumulation of appropriately processed viral proteins. This observation suggests the viral protease is active in the cytoplasmic compartment of the cell. Processing of the Gag protein was blocked in both compartments by the addition of a viral protease inhibitor. A comparison of the amount of cytoplasmic processing seen in lytically infected cells with that seen in chronically infected cells showed that cytoplasmic processing was associated with the lytic infection. These observations raise the possibility that activation of the human immunodeficiency virus type 1 protease in the cytoplasm of lytically infected cells might result in the cleavage of cellular proteins and thus contribute to cytotoxicity.
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PMID:Human immunodeficiency virus type 1 Gag proteins are processed in two cellular compartments. 203 93

Paired serum and saliva samples were tested by enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) for the presence of human immunodeficiency virus (HIV) antibodies. The study group included 36 individuals known to be HIV seropositive and 14 healthy, seronegative controls. HIV antibodies were detected in all but one of the saliva samples of the seropositive subjects. In this particular patient, seroconversion was documented 1 week earlier by sequential testings. A further saliva sample obtained 2 months later was ELISA positive for salivary HIV antibodies. Antibodies against HIV proteins gp120 and gp160 were detected by Western blot assay in all saliva specimens taken from HIV seropositive subjects (including the ELISA-negative patient who seroconverted. Antibodies against other viral proteins (p65, p55, p51, gp41, p35, p24 p18) were found in saliva haphazardly without any clear-cut correlation with the clinical stage of the disease. Pretreatment of the saliva with protease inhibitor was essential for the diagnostic use of saliva for the detection of HIV antibodies by Western blot assay. Calculation of the ratio of titres in serum to those in saliva showed the highest ratios in symptomless subjects (mean +/- SD; 1844 +/- 1412) and the lowest in patients with acquired immune deficiency syndrome (AIDS) (mean +/- SD; 811 +/- 445). The ratio of serum to saliva by ELISA showed a positive correlation with salivary flow rate, indicating a dilution of salivary HIV antibodies with increasing salivary flow rate. The gingival bleeding index was negatively correlated with the ratio, supporting the concept that salivary HIV antibodies transudate from blood to saliva via gingival fluid.
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PMID:HIV antibodies in whole saliva detected by ELISA and western blot assays. 237 May 20

The protease of human immunodeficiency virus has been expressed in Escherichia coli and purified to apparent homogeneity. Immunoreactivity toward anti-protease peptide sera copurified with an activity that cleaved the structural polyprotein gag p55 and the peptide corresponding to the sequence gag 128-135. The enzyme expressed as a nonfusion protein exhibits proteolytic activity with a pH optimum of 5.5 and is inhibited by the aspartic protease inhibitor pepstatin with a Ki of 1.1 microM. Replacement of the conserved residue Asp-25 with an Asn residue eliminates proteolytic activity. Analysis of the minimal peptide substrate size indicates that 7 amino acids are required for efficient peptide cleavage. Size exclusion chromatography is consistent with a dimeric enzyme and circular dichroism spectra of the purified enzyme are consistent with a proposed structure of the protease (Pearl, L.H., and Taylor, W.R. (1987) Nature 329, 351-354). These data support the classification of the human immunodeficiency virus protease as an aspartic protease, likely to be structurally homologous with the well characterized family that includes pepsin and renin.
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PMID:Human immunodeficiency virus protease. Bacterial expression and characterization of the purified aspartic protease. 264 59

Retroviral proteins, including those from the human immunodeficiency virus (HIV), are synthesized as polyprotein precursors that require proteolytic cleavage to yield the mature viral proteins. A 99-residue polypeptide, encoded by the 5' end of the pol gene, has been proposed as the processing protease of HIV. The chemical synthesis of the 99-residue peptide was carried out by the solid-phase method, and the isolated product was found to exhibit specific proteolytic activity upon folding under reducing conditions. Upon size-exclusion chromatography, enzymatic activity was eluted at a point consistent with a dimeric molecular size. Specificity was demonstrated by the cleavage of the natural substrate HIV gag p55 into gag p24 and gag p17, as well as cleavage of small peptide substrates representing processing sites of HIV fusion proteins. The proteolytic action of the synthetic product could be inhibited by pepstatin, an aspartic protease inhibitor.
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PMID:Chemical synthesis and enzymatic activity of a 99-residue peptide with a sequence proposed for the human immunodeficiency virus protease. 305 Sep 88

We recently purified the calcium-independent processing protease named viral envelope glycoprotein maturase (VEM), that converts human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein precursor gp160 to gp120 and gp41, from the human CD4+ T cell line, Molt-4 clone 8 [Kido, H., Kamoshita, K., Fukutomi, A., and Katunuma, N. (1993) J. Biol. Chem. 268, 13406-13413]. In this report, we deal with the inhibitor specificity and calcium requirement for intracellular gp160 processing in cultured HeLa cells and human CD4+ lymphocytes. Processing of gp160 in these cells infected with recombinant vaccinia virus encoding the gp160 gene was not affected by intracellular calcium depletion induced by the calcium ionophore A23187 and EGTA or by intracellular calcium administration. Processing of gp160 by the purified VEM in vitro was not inhibited by EDTA, EGTA, or the metallo-protease inhibitor phosphoramidon, but was specifically inhibited by a substrate analog, decanoyl-RVKR-chloromethylketone, and the trypsin-type protease inhibitors aprotinin, HI-30, and diisopropyl fluorophosphate (DFP). It was also inhibited by E-64 and thiol reagents. But intracellular gp160 processing was inhibited only by permeable, low molecular mass inhibitors of VEM, such as DFP, E-64, and thiol reagents. Syncytium formation induced by cell surface gp120 was also inhibited by permeable inhibitors of VEM. Taken together, our results indicate that calcium ions may not be essential for intracellular gp160 processing and so HIV-1 gp160 induced by recombinant vaccinia virus may be processed mainly by a protease(s) that does not require calcium ions, such as VEM in these cells.
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PMID:Calcium requirement and inhibitor spectrum for intracellular HIV type 1 gp160 processing in cultured HeLa cells and CD4+ lymphocytes: similarity to those of viral envelope glycoprotein maturase. 749 Feb 67


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