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)

Glioblastoma is a therapeutic challenge as a highly infiltrative, proliferative, and resistant tumor. Among novel therapeutic approaches, proteasome inhibition is very promising in controlling cell cycle and inducing apoptosis. This study investigated the effect of ritonavir, a protease inhibitor of the HIV and a proteasome modulator, on glioma cells. The hypothesis was that proteasome modulation, mainly by only inhibiting proteasome chymotrypsin-like activity, could be sufficient to control tumor progression. The experiments were done on a human glioblastoma-derived GL15 cell line and a rat nitrosourea-induced gliosarcoma 9L cell line. Culturing conditions included monolayer cultures, transplantations into brain slices, and transplantations into rat striata. The study demonstrates that ritonavir, by inhibiting the chymotrypsin-like activity of the proteasome, has cytostatic and cytotoxic effects on glioma cells, and can induce resistances in vitro. Ritonavir was unable to control tumor growth in vivo, likely because the therapeutic dose was not reached in the tumor in vivo. Nevertheless, ritonavir might also be beneficial, by decreasing tumor infiltration, in the reduction of the deleterious peritumor edema in glioblastoma.
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PMID:Effects of the proteasome inhibitor ritonavir on glioma growth in vitro and in vivo. 1498 53

Wasting and renal diseases are frequent complications of HIV (human immunodeficiency virus) infection and are associated with accelerated disease progression and increased mortality. Transgenic mice expressing HIV1 under control of the CD4 promoter develop an AIDS-like disease and were used in the present work to study HIV1-induced wasting and kidney pathology. In this study, we reported that disease evolution paralleled increases in serum urea and creatinine levels, indicating an early and progressive deterioration of kidney function; meanwhile the wasting syndrome characterized by up-regulation of the ubiquitine-proteasome pathway and increased level of serum 3-methyl-histidine levels occurred at later stages just prior to death. Further examination of kidney and muscle pathologies revealed a progressive accumulation of CD45(+) cells, first affecting the kidneys. In addition, the onset of disease is accompanied by elevated levels of circulating "regulated on activation, normal and secreted T cell expressed and secreted" (RANTES). These results prompted us to assess the effects of AS602868, a specific small molecule inhibitor of IkappaB kinase 2 (IKK2) on disease progression. Inhibition of the NF-kappaB pathway indeed resulted in increased lifespan, kidney and lean body mass preservation. These beneficial results were associated with a reduction of CD45(+) cells infiltrating the kidneys, amelioration of the renal architecture, and reduced level of circulating RANTES. Together our data provide evidence that IKK2 inhibitors have therapeutic relevance in the treatment of HIV1-associated disorders.
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PMID:IKK2 inhibitor alleviates kidney and wasting diseases in a murine model of human AIDS. 1503 14

The auxiliary regulatory protein Vpr of HIV-1 possesses several biological activities which are believed to facilitate HIV-1 replication and pathogenesis. In this report, experimental evidence suggests a novel biological activity of Vpr: facilitation of the turnover of Vpr mutants bearing the L64P mutation. This novel activity of Vpr was shared by Vpr molecules from different subtypes of HIV-1. Co-expression of the wild type Vpr with the VprW54A/L64P mutant resulted in normal synthesis of the mutant mRNA but enhanced ubiquitination and turnover of the mutant protein. These results suggest that Vpr may interact with the ubiquitin/proteasome pathway to regulate the stability of viral or cellular proteins.
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PMID:HIV-1 auxiliary regulatory protein Vpr promotes ubiquitination and turnover of Vpr mutants containing the L64P mutation. 1506 44

Nuclear Factor-kappa B (NF-kappaB) is an inducible transcription factor of the Rel family, and is sequestered in the cytoplasm by the IkappaB family of proteins. NF-kappaB can exist in several dimeric forms, but the p50/p65 heterodimer is the predominant one. Activation of NF-kappaB by a range of stimuli including viral products, and oxidative stress, leads to phosphorylation and proteasome dependent degradation of IkappaB, leading to the release of free NF-kappaB. This free NF-kappaB then binds to its target sites (KB sites in the DNA) to initiate transcription. These kappaB sites are also present in the Long Terminal Repeat (LTR) of HIV-1, and hence NF-kappaB (p50 subunit) binding to LTR-DNA is critical in viral replication. Targeting direct p50-DNA binding, in this regard, is a novel approach to design anti-HIV gene expression inhibitors, which do not have the problem of resistance unlike in other anti-HIV strategies. The present study is a part of our search for leads for the specific inhibition of p50-DNA binding. We have been experimentally studying different types of these inhibitors, and in this work, we attempted to get a common definition of their structural mechanism onto p50-DNA binding. Using three different classes of inhibitors, we modelled their association with the DNA-Binding Region (DBR) of the p50 subunit of NF-kappaB. Docking studies were carried out using a genetic algorithm based program (GOLD). Further, to compare electrostatic complementarity in the association of the inhibitors with the DBR, Molecular Electrostatic Potentials (MEPs) were generated for the DBR and each inhibitor. The results of docking revealed a strong network of hydrogen bonding interactions for every active inhibitor, and the contrary for the less active ones. Further, the MEPs revealed that the DBR of p50 represents a surface of electropositive potential, and the active inhibitors represent a complementary electronegative surface. With the present modelling study we conclude that the principal properties to be possessed by the new leads against p50-DNA binding should be that of having the ability to make a strong network of hydrogen bonds with the DBR of p50, and preferably, having electronegative potentials in their peripheral surface.
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PMID:A molecular modeling study of inhibitors of nuclear factor kappa-B (p50)--DNA binding. 1512 31

Focal segmental glomerulosclerosis (FSGS) is a common pattern of renal injury, seen as both a primary disorder and as a consequence of underlying insults such as diabetes, HIV infection, and hypertension. Point mutations in the alpha-actinin-4 gene ACTN4 cause an autosomal dominant form of human FSGS. We characterized the biological effect of these mutations by biochemical assays, cell-based studies, and the development of a new mouse model. We found that a fraction of the mutant protein forms large aggregates with a high sedimentation coefficient. Localization of mutant alpha-actinin-4 in transfected and injected cells, as well as in situ glomeruli, showed aggregates of the mutant protein. Video microscopy showed the mutant alpha-actinin-4 to be markedly less dynamic than the wild-type protein. We developed a "knockin" mouse model by replacing Actn4 with a copy of the gene bearing an FSGS-associated point mutation. We used cells from these mice to show increased degradation of mutant alpha-actinin-4, mediated, at least in part, by the ubiquitin-proteasome pathway. We correlate these findings with studies of alpha-actinin-4 expression in human samples. "Knockin" mice with a disease-associated Actn4 mutation develop a phenotype similar to that observed in humans. Comparison of the phenotype in wild-type, heterozygous, and homozygous Actn4 "knockin" and "knockout" mice, together with our in vitro data, suggests that the phenotypes in mice and humans involve both gain-of-function and loss-of-function mechanisms.
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PMID:Alpha-actinin-4-mediated FSGS: an inherited kidney disease caused by an aggregated and rapidly degraded cytoskeletal protein. 1520 19

The Tat protein of human immunodeficiency virus type 1 (HIV-1) is essential for viral replication and activates RNA polymerase II transcriptional elongation through the association with a cellular protein kinase composed of Cdk9 and cyclin T1. Tat binds to this kinase complex through a direct protein-protein interaction with cyclin T1. Monocytes/macrophages are important targets of HIV-1 infection, and previous work has shown that cyclin T1 but not Cdk9 protein expression is low in monocytes isolated from blood. While Cdk9 expression is expressed at a high level during monocyte differentiation to macrophages in vitro, cyclin T1 expression is induced during the first few days of differentiation and is shut off after 1 to 2 weeks. We show here that the shutoff of cyclin T1 expression in late-differentiated macrophages involves proteasome-mediated proteolysis. We also show that cyclin T1 can be reinduced by a number of pathogen-associated molecular patterns that activate macrophages, indicating that up-regulation of cyclin T1 is part of an innate immune response. Furthermore, we found that HIV-1 infection early in macrophage differentiation results in sustained cyclin T1 expression, while infection at late times in differentiation results in the reinduction of cyclin T1. Expression of the viral Nef protein from an adenovirus vector suggests that Nef contributes to the HIV-1 induction of cyclin T1. These findings suggest that HIV-1 infection hijacks a component of the innate immune response in macrophages that results in enhancement rather than inhibition of viral replication.
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PMID:Human immunodeficiency virus type 1 infection induces cyclin T1 expression in macrophages. 1525 83

The Vpu protein is the smallest of the proteins encoded by human immunodeficiency virus type 1 (HIV-1). This transmembrane protein interacts with the CD4 molecule in the rough endoplasmic reticulum (RER), resulting in its degradation via the proteasome pathway. Vpu also has been shown to enhance virion release from infected cells. While much has been learned about the function of Vpu in cell culture systems, its exact role in HIV-1 pathogenesis is still unknown. This has been primarily due to the lack of a suitable primate model system since vpu is found only in HIV-1 and simian immunodeficiency viruses isolated from chimpanzees (SIVcpz), and three species of old world monkeys within the genus Cercopithecus. Several laboratories have developed pathogenic molecular clones of simian-human immunodeficiency virus (SHIV) in which the tat, rev, vpu and env genes of HIV-1 are expressed in the genetic background of SIV. The availability of such clones has allowed investigators to assess the role of Vpu in pathogenesis using a relevant animal model. This review will focus on the current understanding of the structure-function relationships of Vpu protein and recent advances using the SHIV model to assess the role of Vpu in HIV-1 pathogenesis.
Curr HIV Res 2004 Jul
PMID:Vpu: a multifunctional protein that enhances the pathogenesis of human immunodeficiency virus type 1. 1527 89

Plasma cell disorders are not uncommonly reported in young patients with HIV infection. These disorders range from benign polyclonal hypergammaglobulinemia to indeterminate monoclonal gammopathy of unknown significance (MGUS) to malignant dyscrasias, including multiple myeloma and plasma cell leukemia. Hypergammaglobulinemia and oligoclonal banding had been the most frequently reported disorders in the pre-HAART era. In HIV-infected persons, the incidence of MGUS is reported to be around 2.5%, with an approximate 4.5-fold increased risk of multiple myeloma. Many of these HIV-infected patients had been treated with alkylator-based regimens, and these reports predate the current widespread use of thalidomide-dexamethasone combination treatment in multiple myeloma. Although the optimal therapy for an HIV-infected person might with plasma cell dyscrasia is yet to be defined, in the current era of HAART the otherwise healthy HIV-infected patient might be tested like an HIV-negative person. Consequently, treatment with immunomodulatory agents (eg, thalidomide) and proteasome inhibitors (eg, bortezomib) may also be worth considering. High-dose chemotherapy with an autologous peripheral blood stem cell transplant is increasingly being considered as consolidation therapy in the younger non-HIV-infected myeloma patient. In the next few years, it is anticipated that these approaches will be applied more frequently to HIV-infected persons with myeloma.
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PMID:Plasma cell disorders in HIV-infected patients: from benign gammopathy to multiple myeloma. 1528 66

In 1995, we discovered new antiherpetic antibiotics, called fattiviracins. The producing organism was classified as a strain belonging to Streptomyces microflavus. The strain produced at least 13 fattiviracin derivatives (FV-1 to FV-13). Fattiviracins were obtained as a white amorphous powder, and their molecular weights are in the range of 1400 to 1500. They are readily soluble in water, methanol, pyridine, and DMSO, but insoluble in other organic solvents. Fattiviracins have macrocyclic diesters formed by the binding of two trihydroxy fatty acids and two D-glucose residues in the molecule, and they can be divided into five families according to the length of the fatty acid moiety. Fattiviracins have potent activity against enveloped DNA viruses such as the herpes family, HSV-1, and VZV and enveloped RNA viruses such as influenza A and B viruses, and three strains of HIV-1, with EC(50) values on the order of a few micrograms per milliliter. The biosynthetic pathway of fattiviracins is also becoming clearer. Using bacitracin-resistant strains, enhanced and astringent production of fattiviracin was achieved. Fattiviracin FV-13, which has the longest fatty acid chains in the molecule, was dramatically enhanced by a C(55)-isoprenyl phosphate metabolism. In addition, we have screened various inhibitors of enzymes such as alkaline protease, glucosyltransferase, glucuronidase, phospholipase, deoxyribonuclease, DNA methyltransferase, and DNA topoisomerase. All the inhibitors we discovered are briefly summarized in this paper.
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PMID:[Metabolites produced by actinomycetes--antiviral antibiotics and enzyme inhibitors]. 1529 17

Tat, the trans activation protein of HIV, is produced early upon infection to promote and expand HIV replication and transmission. However, Tat appears to also have effects on target cells, which may affect Ag recognition both during infection and after vaccination. In particular, Tat targets dendritic cells and induces their maturation and Ag-presenting functions, increasing Th1 T cell responses. We show in this work that Tat modifies the catalytic subunit composition of immunoproteasomes in B and T cells either expressing Tat or treated with exogenous biological active Tat protein. In particular, Tat up-regulates latent membrane protein 7 and multicatalytic endopeptidase complex like-1 subunits and down-modulates the latent membrane protein 2 subunit. These changes correlate with the increase of all three major proteolytic activities of the proteasome and result in a more efficient generation and presentation of subdominant MHC-I-binding CTL epitopes of heterologous Ags. Thus, Tat modifies the Ag processing and modulates the generation of CTL epitopes. This may have an impact on both the control of virally infected cells during HIV-1 infection and the use of Tat for vaccination strategies.
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PMID:HIV-1 tat protein modulates the generation of cytotoxic T cell epitopes by modifying proteasome composition and enzymatic activity. 1535 31


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