Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of several cytokines involved in signal transduction such as TGFbeta-1 and the inflammatory chemokines including MCP-1 is elevated during the course of AIDS progression. The enhancement of these cellular proteins in astrocytic cells is mediated, at least in part, by HIV-1 Tat protein. Here, we investigate the possible regulation of MCP-1 transcription by Tat and the Smad family of transcription factors whose activities are induced by the TGFbeta-1 pathway. Results from transfection studies revealed that Smad-3 stimulates basal and Tat-mediated transcription of MCP-1 in human astrocytic cells. Smad-4, on the other hand, had no effect on the basal activity of the MCP-1 promoter, but showed the ability to decrease both Smad-3 and Tat-induced transcription of the MCP promoter. Results from protein-binding studies revealed the ability of both Smad-3 and Smad-4 to associate with the region of Tat spanning residues 1-40. Examination of the transcriptional activity of the various domains of Smad including MH1, at the N-terminus, and MH2, at the C-terminus of the protein indicated that neither MH1 or MH2 alone positively cooperate with Tat in modulating MCP-1 transcription. However, ectopic expression of MH1 and, more notably, MH2 severely suppressed transcriptional activation of MCP-1 by Tat in astrocytic cells. Binding studies revealed that similar to the full-length Smad protein, both MH1 and MH2 associate with Tat protein and that the residues between 1 and 40 of Tat are important for their interaction. These observations reveal a novel mechanism for Tat-mediated transcriptional activation via TGFbeta signaling pathway and provide evidence for regulation of MCP-1 gene transcription by this signaling pathway in human astrocytic cells.
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PMID:Regulation of MCP-1 gene transcription by Smads and HIV-1 Tat in human glial cells. 1275 67

This study identifies calpain as being instrumental for brush border (BB) microvillus assembly during differentiation and effacement during bacterial pathogenesis. Calpain activity is decreased by 25-80% in Caco 2 lines stably overexpressing calpastatin, the physiological inhibitor of calpain, and the effect is proportional to the calpastatin/calpain ratio. These lines exhibit a 2.5-fold reduction in the rate of microvillus extension. Apical microvillus assembly is reduced by up to 50%, as measured by quantitative fluorometric microscopy (QFM) of ezrin, indicating that calpain recruits ezrin to BB microvilli. Calpain inhibitors ZLLYCHN2, MDL 28170, and PD 150606 block BB assembly and ezrin recruitment to the BB. The HIV protease inhibitor ritonavir, which inhibits calpain at clinically relevant concentrations, also blocks BB assembly, whereas cathepsin and proteasome inhibitors do not. Microvillus effacement is inhibited after exposure of calpastatin-overexpressing cells to enteropathogenic Escherichia coli. These results suggest that calpain regulates BB assembly as well as pathological effacement, and indicate that it is an important regulator involved in HIV protease inhibitor toxicity and host-microbial pathogen interactions.
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PMID:Calpain regulates enterocyte brush border actin assembly and pathogenic Escherichia coli-mediated effacement. 1276 39

A series of new 7-substituted-4-chloro-3-alkoxy isocoumarin derivatives were synthesized and evaluated as inhibitors of representative classes of proteases: serine protease (alpha-chymotrypsin, trypsin), cysteine protease (Caspase-3), and aspartyl protease (HIV-protease), 20S proteasome and also as inhibitors of amyloid peptide gamma-secretase-mediated production. Protease inhibition selectivity is directly related to the structure of the substituent at the 7-position of the isocoumarin nucleus. 7-Nitro-isocoumarin derivatives (4c, 4d, 4f) are potent alpha-chymotrypsin inhibitors but slightly active or inactive on HIV-protease, as well as on cysteine protease. In contrast, only derivatives bearing a free amino (5d, 5f) or a substituted amino group (6f) at the 7-position of the isocoumarin nucleus, were found weakly active or inactive on alpha-chymotrypsin, trypsin, Caspase-3 and HIV-protease, but prevent gamma-secretase-mediated production of Abeta 40/42 amyloid peptides, which is known to be involved in Alzheimer's disease. Moreover, the most active compounds on beta-amyloid peptide production [JLK6 (5d), JLK2 (5f) and JLK7 (6f)] show only weak or moderate inhibitory activity on the 20S proteasome. The obtained results suggest that the described new isocoumarin analogues could be of interest, since compounds like JLK6 (5d), JLK2 (5f) and JLK7 (6f) can be considered as possible hits for the development of new agents directed towards Alzheimer's disease.
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PMID:Synthesis of new 3-alkoxy-7-amino-4-chloro-isocoumarin derivatives as new beta-amyloid peptide production inhibitors and their activities on various classes of protease. 1281 77

HIV-1 is a fundamentally difficult target for vaccines because of its high mutation rate and its repertoire of immune evasion strategies. To address these difficulties, a multivalent genetic vaccine or "live genetic vaccine" was recently developed against HIV-1 using the expression library immunization (ELI) approach. In this HIV-1 vaccine, all open reading frames of HTLV-IIIb are expressed as protein fragments to retain all viral T cell epitopes, but destroy protein toxicity, inactivate immune escape functions, and reveal subdominant epitopes. In addition, each antigen fragment is fused to the ubiquitin protein to increase antigen expression and target these antigens to the proteasome to enhance cytotoxic T lymphocyte (CTL) responses. This multivalent vaccine also has the advantage of being incapable of generating infectious HIV-1 virus because of the segregation of the HIV genome into 32 separate plasmids. In this work, we demonstrate the ability of this genetic vaccine to provoke robust HLA-A*0201-restricted T cell responses in MHC class I humanized mice against gag, pol, env, and nef after a single round of immunization. In addition, this HTLV-IIIb-derived vaccine demonstrated cross-clade, envelope-specific, HLA-restricted CD8 responses against clades A, D, and E. HLA-restricted CD8 responses were generated against all 32 open reading frames encoded by the multi-plasmid genetic vaccine demonstrating that a broad repertoire of human relevant CD8 responses are provoked by this vaccine. This work supports this approach to generate multivalent T cell responses to control the highly mutable and immuno-evasive HIV-1 virus.
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PMID:Generation of multivalent genome-wide T cell responses in HLA-A*0201 transgenic mice by an HIV-1 expression library immunization (ELI) vaccine. 1284 72

HIV lipodystrophy is a heterogeneous syndrome, which has yet to be objectively defined, comprising peripheral lipoatrophy, central fat accumulation and lipomata, along with hyperlipidaemia, insulin resistance and lactic acidaemia. Both nucleoside analogues and protease inhibitors are involved, but there are also host factors that probably place some patients at greater risk. The pathogenesis is increasingly understood, with evidence of interference of several regulatory proteins such as sterol regulatory enhancer binding protein-1, the proteasome, mitochondrial DNA polymerase gamma and GLUT-4. Along with the issues of cosmesis and stigmatization, a principal clinical concern that arises with lipodystrophy is a possible increased risk of accelerated atherosclerosis. A variety of therapeutic interventions, designed to limit these risks, are under evaluation, but none is conclusively shown to be of value.
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PMID:HIV lipodystrophy: risk factors, pathogenesis, diagnosis and management. 1287 May 40

HIV protease inhibitors are antiretroviral drugs that block the enzyme required for production of infectious viral particles. Although these agents have been designed to selectively bind to the catalytic site of HIV protease, evidence indicates that other cellular and microbial enzymes and pathways are also affected. It has been reported that patients treated with highly active anti-retroviral therapy (HAART) containing a protease inhibitor may be at reduced risk of Kaposi's sarcoma (KS) and some types of non-Hodgkin lymphomas; some disease regressions have also been described. Here we review recent data showing that several widely used protease inhibitors, including indinavir, saquinavir, ritonavir, and nelfinavir, can affect important cellular and tissue processes such as angiogenesis, tumour growth and invasion, inflammation, antigen processing and presentation, cell survival, and tissue remodelling. Most of these non-HIV-related effects of protease inhibitors are due to inhibition of cell invasion and matrix metalloprotease activity, or modulation of the cell proteasome and NFkappaB. These elements are required for development of most tumours. Thus, by direct and indirect activities, protease inhibitors can simultaneously block several pathways involved in tumour growth, invasion, and metastasis. These findings indicate that protease inhibitors can be exploited for the therapy of KS and other tumours that occur in both HIV-infected and non-infected individuals. A multicentre phase II clinical trial with indinavir in non-HIV-associated KS is about to start in Italy.
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PMID:Use of HIV protease inhibitors to block Kaposi's sarcoma and tumour growth. 1296 74

The human immunodeficiency virus type 1 (HIV-1) relies on Vif (viral infectivity factor) to overcome the potent antiviral function of APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G, also known as CEM15). Using an APOBEC3G-specific antiserum, we now show that Vif prevents virion incorporation of endogenous APOBEC3G by effectively depleting the intracellular levels of this enzyme in HIV-1-infected T cells. Vif achieves this depletion by both impairing the translation of APOBEC3G mRNA and accelerating the posttranslational degradation of the APOBEC3G protein by the 26S proteasome. Vif physically interacts with APOBEC3G, and expression of Vif alone in the absence of other HIV-1 proteins is sufficient to cause depletion of APOBEC3G. These findings highlight how the bimodal translational and posttranslational inhibitory effects of Vif on APOBEC3G combine to markedly suppress the expression of this potent antiviral enzyme in virally infected cells, thereby effectively curtailing the incorporation of APOBEC3G into newly formed HIV-1 virions.
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PMID:HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability. 1452 6

The human protein apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like-3G (APOBEC3G), also known as CEM-15, mediates a newly described form of innate resistance to retroviral infection by catalyzing the deamination of deoxycytidine to deoxyuridine in viral cDNA replication intermediates. Because DNA deamination takes place after virus entry into target cells, APOBEC3G function is dependent on its association with the viral nucleoprotein complexes that synthesize cDNA and must therefore be incorporated into virions as they assemble in infected cells. Here we show that the HIV-1 virion infectivity factor (Vif) protein protects the virus from APOBEC3G-mediated inactivation by preventing its incorporation into progeny virions, thus allowing the ensuing infection to proceed without DNA deamination. In addition to helping exclude APOBEC3G from nascent virions, Vif also removes APOBEC3G from virus-producing cells by inducing its ubiquitination and subsequent degradation by the proteasome. Our findings indicate that pharmacologic strategies aimed at stabilizing APOBEC3G in HIV-1 infected cells should be explored as potential HIV/AIDS therapeutics.
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PMID:The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif. 1452

The viral infectivity factor (Vif) encoded by HIV-1 neutralizes a potent antiviral pathway that occurs in human T lymphocytes and several leukemic T-cell lines termed nonpermissive, but not in other cells termed permissive. In the absence of Vif, this antiviral pathway efficiently inactivates HIV-1. It was recently reported that APOBEC3G (also known as CEM-15), a cytidine deaminase nucleic acid-editing enzyme, confers this antiviral phenotype on permissive cells. Here we describe evidence that Vif binds APOBEC3G and induces its rapid degradation, thus eliminating it from cells and preventing its incorporation into HIV-1 virions. Studies of Vif mutants imply that it contains two domains, one that binds APOBEC3G and another with a conserved SLQ(Y/F)LA motif that mediates APOBEC3G degradation by a proteasome-dependent pathway. These results provide promising approaches for drug discovery.
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PMID:HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation. 1452 1

The human immunodeficiency virus-1 (HIV-1) Tat protein was previously reported to compete the association of PA28 regulator with the alpha rings of the 20S proteasome and to inhibit its peptidase activity. However, the distinct interaction sites within the proteasome complex remained to be determined. Here we show that HIV-1 Tat binds to alpha4 and alpha7, six beta subunits of the constitutive 20S proteasome and the interferon-gamma-inducible subunits beta2i and beta5i. A Tat-proteasome interaction can also be demonstrated in vivo and leads to inhibition of proteasomal activity. This indicates that Tat can modulate or interfere with cellular proteasome function by specific interaction with distinct proteasomal subunits.
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PMID:Human immunodeficiency virus-1 Tat protein interacts with distinct proteasomal alpha and beta subunits. 1455 May 73


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