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)

HIV and many other enveloped viruses encode a late budding domain (L-domain) that recruits the cellular machinery that mediates the separation of the nascent virion from the infected cell. The ubiquitin-proteasome system has been implicated in the L-domain activity, but the exact role of ubiquitin transfer and ubiquitin-binding proteins in the last step of viral replication remains elusive. It is now widely accepted that the class E vacuolar protein sorting pathway mediates both viral budding and vesicle budding into the multivesicular bodies and, remarkably, both budding events share the same topology and similar requirements for ubiquitin. In this review, the role of ubiquitin in viral budding is discussed in the light of recent advances in the understanding of the cellular mechanisms that assist the last step of HIV-1 release.
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PMID:The role of ubiquitin in retroviral egress. 1764 37

Viral protein U (Vpu) of HIV-1 has two known functions in replication of the virus: degradation of its cellular receptor CD4 and enhancement of viral particle release. Vpu binds CD4 and simultaneously recruits the betaTrCP subunit of the SCF(betaTrCP) ubiquitin ligase complex through its constitutively phosphorylated DS52GXXS56 motif. In this process, Vpu was found to escape degradation, while inhibiting the degradation of betaTrCP natural targets such as beta-catenin and IkappaBalpha. We further addressed this Vpu inhibitory function with respect to the degradation of Emi1 and Cdc25A, two betaTrCP substrates involved in cell-cycle progression. In the course of these experiments, we underscored the importance of a novel phosphorylation site in Vpu. We show that, especially in cells arrested in early mitosis, Vpu undergoes phosphorylation of the serine 61 residue, which lies adjacent to the betaTrCP-binding motif. This phosphorylation event triggers Vpu degradation by a betaTrCP-independent process. Mutation of Vpu S61 in the HIV-1 provirus extends the half-life of the protein and significantly increases the release of HIV-1 particles from HeLa cells. However, the S61 determinant of regulated Vpu turnover is highly conserved within HIV-1 isolates. Altogether, our results highlight a mechanism where differential phosphorylation of Vpu determines its fate as an adaptor or as a substrate of distinct ubiquitin ligases. Conservation of the Vpu degradation determinant, despite its negative effect on virion release, argues for a role in overall HIV-1 fitness.
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PMID:Regulated degradation of the HIV-1 Vpu protein through a betaTrCP-independent pathway limits the release of viral particles. 1767 96

The role of the Human Immunodeficiency Virus (HIV) in the pathogenesis of the Acquired Immune-Deficiency Syndrome (AIDS) is changed. Direct HIV-mediated killing of CD4(+) T cells is not the only mechanism leading to lymphocyte depletion. There is increasing evidence that, during the chronic phases of infection, T cell activation, accelerated cell turnover, and cytokines imbalance induce the so-called cell cycle dysregulation (CCD). CCD is a recently discovered immune-pathogenic mechanism that mainly induces the depletion of both CD4(+) and CD8(+) uninfected T cells. It is due to a significant perturbation of protein metabolism as ubiquitin pathway defects of protein degradation are associated with an increased and unscheduled expression of cyclin B and p34 cdc kinase. Moreover, significant changes in the nucleolar structure and post-translational regulation of nucleolin have also been described. As modulation of CCD by anti-retroviral and immune-therapies has been suggested to predict a good immunological response in HIV-infected patients, a better understanding of such a mechanism is needed in order to further clarify its role in the pathogenesis and progression of HIV infection.
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PMID:New insights on the perturbations of T cell cycle during HIV infection. 1769 34

HIV-1 integrase, the viral enzyme responsible for provirus integration into the host genome, can be actively degraded by the ubiquitin-proteasome pathway. Here, we identify von Hippel-Lindau binding protein 1(VBP1), a subunit of the prefoldin chaperone, as an integrase cellular binding protein that bridges interaction between integrase and the cullin2 (Cul2)-based von Hippel-Lindau (VHL) ubiquitin ligase. We demonstrate that VBP1 and Cul2/VHL are required for proper HIV-1 expression at a step between integrase-dependent proviral integration into the host genome and transcription of viral genes. Using both an siRNA approach and Cul2/VHL mutant cells, we show that VBP1 and the Cul2/VHL ligase cooperate in the efficient polyubiquitylation of integrase and its subsequent proteasome-mediated degradation. Results presented here support a role for integrase degradation by the prefoldin-VHL-proteasome pathway in the integration-transcription transition of the viral replication cycle.
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PMID:von Hippel Lindau binding protein 1-mediated degradation of integrase affects HIV-1 gene expression at a postintegration step. 1769 9

The molecular mechanisms of action of a HIV protease inhibitor, ritonavir, on hepatic function were explored on a genomic scale using microarrays comprising genes expressed in the liver of Sprague-Dawley rats (Rattus norvegicus). Analyses of hepatic transcriptional fingerprints led to the identification of several key cellular pathways affected by ritonavir treatment. These effects were compared to a compendium of gene expression responses for 52 unrelated compounds and to other protease inhibitors, including atazanavir and two experimental compounds. We identified genes involved in cholesterol and fatty acid biosynthesis, as well as genes involved in fatty acid and cholesterol breakdown, whose expressions were regulated in opposite manners by ritonavir and bezafibrate, a hypolipidemic agonist of the peroxisome proliferator-activated receptor alpha. Ritonavir also upregulated multiple proteasomal subunit transcripts as well as genes involved in ubiquitination, consistent with its known inhibitory effect on proteasomal activity. We also tested three other protease inhibitors in addition to ritonavir. Atazanavir did not impact ubiquitin or proteasomal gene expression, although the two other experimental protease inhibitors impacted both proteasomal gene expression and sterol regulatory element-binding protein-activated genes, similar to ritonavir. Identification of key metabolic pathways that are affected by ritonavir and other protease inhibitors will enable us to understand better the downstream effects of protease inhibitors, thus leading to better drug design and an effective method to mitigate the side effects of this important class of HIV therapeutics.
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PMID:Gene expression profiling of rat liver reveals a mechanistic basis for ritonavir-induced hyperlipidemia. 1771

Human immunodeficiency virus tyoe 1 (HIV-1) Vif counteracts host restriction cytidine deaminase (APOBEC3G) A3G by co-opting the cellular ubiquitin-proteasome machinery. Vif utilizes a viral-specific BC-box to recruit ElonginB-ElonginC and a novel zinc-binding HCCH motif to recruit Cullin5 (Cul5) to form an E3 ubiquitin ligase targeting A3G for polyubiquitination and subsequently proteasomal degradation. To determine the structural requirements in HIV-1 Vif HCCH motif for Cul5 binding and Vif function, we investigated the arrangement of the His and Cys residues, the role of the spacing between them, and the requirement for the conserved residues. Our data demonstrate that exchanging Cys for His and vice versa in the highly conserved Zn-coordinating HCCH motif disrupted Vif function and interaction with Cul5. Moreover, the maintenance of both conserved residues and spacing within the HCCH motif is critical for Vif function. We have identified a "viral Cul5 box" with consensus Hx2YFxCFx4Phix2APhix7-8Cx5H that is required for Cul5 selection and subsequent A3G degradation. This novel motif may represent a potential new target for anti-viral drug development.
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PMID:Characterization of a novel Cullin5 binding domain in HIV-1 Vif. 1786 71

Although alcohol drinking increases susceptibility to human immunodeficiency virus (HIV) infection, possible mechanisms underlying the effects of alcohol are not yet known. Since the HIV envelope protein gp120 plays a key role in progression of HIV infection, the aim of the present study was to evaluate the toxicity and degradation of gp120 in hepatocytes isolated from liver of alcohol-preferring rats drinking either 15% ethanol in water or pure water for 70 days. The hypothesis was that alcohol drinking augmented the toxicity, but suppressed degradation of gp120. Hepatocytes from water-drinking rats (C-cells) or ethanol-drinking rats (Et-cells) were treated with laptacystin, anti-CD4 antibodies, CCR5 antagonist, or mannose, followed by [(125)I]gp120 or native gp120. At predetermined intervals, control (C) and ethanol exposed (Et) cells were analyzed for toxicity and degradation of gp120. In C-cells, [(125)I]gp120 binding and internalization peaked within 5-45 min and remained elevated for up to 10h and then decreased gradually. In Et-cells, [(125)I]gp120 binding peaked comparably to C-cells, but the binding remained to the peak level throughout the experimental period. C-cells exhibited the lysosomal/ubiquitin-mediated degradation of intracellular gp120, resulting in released gp120 fragments into the incubation medium that suppressed gp120-CD4 binding, improved cell viability, and inhibited gp120-induced apoptosis. Ethanol drinking suppressed gp120 degradation in and release of gp120 fragments from hepatocytes. The incubation medium of Et-cells did not suppress gp120-CD4 binding or the gp120-mediated apoptosis in hepatocytes. Thus, chronic alcohol drinking augmented the adverse effects of gp120 possibly by suppressing its degradation in hepatocytes. The present observation also suggests that a number of CCR5 or ubiquitin-based therapeutic drugs may not be effective in suppressing HIV infection in alcohol-drinking subjects.
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PMID:Effects of chronic alcohol drinking on receptor-binding, internalization, and degradation of human immunodeficiency virus 1 envelope protein gp120 in hepatocytes. 1798 Sep 97

The recently identified RNF125 [RING (really interesting new gene) finger protein 125], or TRAC-1 (T-cell RING protein in activation 1), is unique among ubiquitin ligases in being a positive regulator of T-cell activation. In addition, TRAC-1 has been shown to down-modulate HIV replication and to inhibit pathogen-induced cytokine production. However, apart from the presence of an N-terminal C3HC4 (Cys(3)-His-Cys(4)) RING domain, the TRAC-1 protein remains uncharacterized. In the present paper, we report novel interactions and modifications for TRAC-1, and elucidate its domain organization. Specifically, we determine that TRAC-1 associates with membranes and is excluded from the nucleus through myristoylation. Our data are further consistent with a crucial role for the C-terminus in TRAC-1 function. In this region, novel domains were recognized through the identification of three closely related proteins: RNF114, RNF138 and RNF166. TRAC-1 and its relatives were found to contain, apart from the RING domain, a C2HC (Cys(2)-His-Cys)- and two C2H2 (Cys(2)-His(2))-type zinc fingers, as well as a UIM (ubiquitin-interacting motif). The UIM of TRAC-1 binds Lys(48)-linked polyubiquitin chains and is, together with the RING domain, required for auto-ubiquitination. As a consequence of auto-ubiquitination, the half-life of TRAC-1 is shorter than 30 min. The identification of these novel modifications, interactions, domains and relatives significantly widens the contexts for investigating TRAC-1 activity and regulation.
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PMID:T-cell regulator RNF125/TRAC-1 belongs to a novel family of ubiquitin ligases with zinc fingers and a ubiquitin-binding domain. 1799 Sep 82

The activation of IRF-3 during the early stages of viral infection is critical for the initiation of the antiviral response; however the activation of IRF-3 in HIV-1 infected cells has not yet been characterized. We demonstrate that the early steps of HIV-1 infection do not lead to the activation and nuclear translocation of IRF-3; instead, the relative levels of IRF-3 protein are decreased due to the ubiquitin-associated proteosome degradation. Addressing the molecular mechanism of this effect we show that the degradation is independent of HIV-1 replication and that virion-associated accessory proteins Vif and Vpr can independently degrade IRF-3. The null mutation of these two genes reduced the capacity of the HIV-1 virus to down modulate IRF-3 levels. The degradation was associated with Vif- and Vpr-mediated ubiquitination of IRF-3 and was independent of the activation of IRF-3. N-terminal lysine residues were shown to play a critical role in the Vif- and Vpr-mediated degradation of IRF-3. These data implicate Vif and Vpr in the disruption of the initial antiviral response and point to the need of HIV-1 to circumvent the antiviral response during the very early phase of replication.
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PMID:HIV-1 accessory proteins VPR and Vif modulate antiviral response by targeting IRF-3 for degradation. 1808 65

The main source for endogenous peptides presented by the MHC class I (MHC-I) pathway are de novo-synthesized proteins which are degraded via the ubiquitin proteasome pathway. Different MHC-I Ag pools can be distinguished: first, short-lived defective ribosomal products, which are degraded in concert with or shortly after their synthesis, and, second, functional proteins that enter the standard protein life cycle. To compare the contribution of these two Ag sources to the generation of MHC-I-presented peptides, we established murine cell lines which express as a model Ag the HIV-1 Gag polyprotein fused to ubiquitin (Ub) carrying the epitope SIINFEKL (SL). Gag was expressed either in its wild-type form (UbMGagSL) or as a variant UbRGagSL harboring an N-end rule degron signal. Although UbRGagSL displayed wild-type protein stability, its inherent defective ribosomal products rate observed after proteasome shutdown was increased concomitant with enhanced presentation of the SL epitope. In addition, UbRGagSL induces enhanced T cell stimulation of SL-specific B3Z hybridoma cells as measured in vitro and of adoptively transferred TCR-transgenic OT-1 T cells in vivo. Furthermore, an elevated frequency of SL-specific T cells was detected by IFN-gamma ELISPOT after immunization of naive C57BL/6 mice with UbRGagSL/EL4 cells. These results further underline the role of the defective ribosomal product pathway in adaptive immunity.
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PMID:Targeting HIV-1 Gag into the defective ribosomal product pathway enhances MHC class I antigen presentation and CD8+ T cell activation. 1809 38


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