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)

Human immunodeficiency virus 1 (HIV-1) encodes a gene product, Vpr, that facilitates the nuclear uptake of the viral pre-integration complex in non-dividing cells and causes infected cells to arrest in the G(2) phase of the cell cycle. Vpr was also shown to cause mitochondrial dysfunction in human cells and budding yeasts, an effect that was proposed to lead to growth arrest and cell killing in budding yeasts and apoptosis in human cells. In this study, we used a genetic selection in Saccharomyces cerevisiae to identify hexameric peptides that suppress the growth arrest phenotype mediated by Vpr. Fifteen selected glutathione S-transferase (GST)-fused peptides were found to overcome to different extents Vpr-mediated growth arrest. Amino acid analysis of the inhibitory peptide sequences revealed the conservation of a di-tryptophan (diW) motif. DiW-containing GST-peptides interacted with Vpr in GST pull-down assays, and their level of interaction correlated with their ability to overcome Vpr-mediated growth arrest. Importantly, Vpr-binding GST-peptides were also found to alleviate Vpr-mediated apoptosis and G(2) arrest in HIV-1-producing CD4(+) T cell lines. Furthermore, they co-localized with Vpr and interfered with its nuclear translocation. Overall, this study defines a class of diW-containing peptides that inhibit HIV-1 Vpr biological activities most likely by interacting with Vpr and interfering with critical protein interactions.
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PMID:Genetic selection of peptide inhibitors of human immunodeficiency virus type 1 Vpr. 1237 52

Ethanol may have significant effects on human immunodeficiency virus type I (HIV-1) pathogenesis in vivo. As such, the effects of ethanol treatment were studied on the proapoptotic potential of various HIV-1 proteins in primary isolated human brain microvascular endothelial cells (MVECs), a major cellular component of the blood-brain barrier. Low-passage primary brain MVECs were treated with recombinant HIV-1 proteins Nef, Vpr, Tat and gp120 proteins from X4, R5, and X4R5 viral strains, with and without ethanol at various relevant concentrations. The apoptotic potential of each HIV-1 protein with and without ethanol was compared with cells treated with ethanol alone or GST protein as a control, under similar conditions. Specific HIV-1 proteins induced apoptosis in primary isolated human brain MVECs, which was potentiated on treatment with 0.1 and 0.3% (v/v) ethanol. Cotreatment with ethanol and specific HIV-1 proteins showed enhanced lactate dehydrogenase release, compared with MVECs treated with ethanol alone. The presence of ethanol in in vitro culture medium also enhanced HIV-1 protein-mediated tumor necrosis factor-alpha production, compared with cells treated with ethanol alone or GST protein. Thus, these studies demonstrate ethanol's potential for inducing apoptosis of human MVECs with relevant HIV-1-specific proteins and suggest a potential synergistic effect in augmenting HIV-1 neuroinvasion and neuropathogenesis in vivo.
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PMID:Ethanol strongly potentiates apoptosis induced by HIV-1 proteins in primary human brain microvascular endothelial cells. 1250 64

We have recently described a biochemical detection method for peptide products of enzymatic reactions based on the formation of PDZ domain*peptide ligand complexes. The product sensor is based on using masked or cryptic PDZ domain peptide ligands as enzyme substrates. Upon enzymatic processing, a PDZ-binding motif is exposed, and the product sequence bound specifically by a Eu(3+)chelate-labeled GST-PDZ ([Eu(3+)]GST-PDZ). The practical applicability of this PDZ-based detection method is determined by the affinity of the PDZ domain*peptide ligand interaction, and the efficiency of the enzyme to process the masked peptide ligand. To expand the use of this PDZ-based detection strategy to a broader range of enzymatic assays, we have taken advantage of the plasticity in ligand recognition by the variety of PDZ domains found in nature. In the original work, the PDZ3 of PSD-95 was used, which preferentially recognizes the consensus sequence Ser-X-Val-COOH. Here, we show that NHERF PDZ1, which binds to the consensus sequence Thr/Ser-X-Leu-COOH, can be used to extend the flexibility in the recognition of the carboxy-terminal amino acid of the ligand, and monitor the enzymatic activity of HIV protease. The choices of detection format, for example, TRET or ALPHA, were also investigated and influenced assay design.
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PMID:A PDZ domain-based assay for measuring HIV protease activity: assay design considerations. 1259 16

Feline immunodeficiency virus (FIV), like other members of the lentivirus subfamily, such as human immunodeficiency virus type 1 (HIV-1), can infect nondividing and terminally differentiated cells. The transport of the preintegration complex into the nucleus is cell cycle-independent, but the mechanism is not well understood. Integrase is a key component of the complex and has been suggested to play a role in nuclear import during HIV-1 replication. To determine its karyophilic property, FIV integrase fused with glutathione S-transferase and enhanced green fluorescent protein was expressed in various feline and human cells and the subcellular localization was visualized by fluorescence microscopy. Wild-type FIV integrase was karyophilic in all cell lines tested and capable of targeting the fusion protein to the nuclei of transfected cells. Analysis of deletion and point mutation variants of FIV integrase failed to reveal any canonical nuclear localization signal, and the karyophilic determinant was mapped to the highly conserved N-terminal zinc-binding HHCC motif. A region near the C-terminal domain enriched with basic amino acid residues also affected the nuclear import of integrase. However, the role of this region is only modulatory in comparison to that of the zinc-binding domain. The N-terminal zinc-binding domain does not bind DNA and instead is essential in integrase multimerization. We therefore postulate that the karyophilic property of FIV integrase requires subunit multimerization promoted by the HHCC motif. Alternatively, the HHCC motif may directly promote interaction between FIV integrase and cellular proteins involved in nuclear import.
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PMID:Subcellular localization of feline immunodeficiency virus integrase and mapping of its karyophilic determinant. 1266 58

We have previously reported that the host uracil DNA glycosylase UNG2 enzyme is incorporated into HIV-1 virions via a specific association with the viral integrase (IN) domain of Gag-Pol precursor. In this study, we investigated whether UNG2 was packaged into two phylogenetically closely related primate lentiviruses, HIV-2(ROD) and SIV(MAC239). We demonstrated by GST-pull-down and coprecipitation assays that INs from HIV-1, HIV-2(ROD), and SIV(MAC239) associated with UNG2, although the interaction of UNG2 with HIV-2(ROD) IN and SIV(MAC239) IN was less strong than with HIV-1 IN. We then showed by Western blotting that highly purified HIV-2 and SIV(MAC) viral particles did not incorporate host UNG2, contrasting with the presence of UNG2 in HIV-1 viral particles. Finally, we showed that HIV-1/SIV chimeric viruses in which residues 6 to 202 of HIV-1 IN were replaced by the SIV counterpart were impaired for packaging of UNG2, indicating that the incorporation of host UNG2 into viral particles is the hallmark of the HIV-1 strain. Moreover, we found that HIV-1/SIV IN chimeric viruses were deficient for viral propagation.
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PMID:Differential incorporation of uracil DNA glycosylase UNG2 into HIV-1, HIV-2, and SIV(MAC) viral particles. 1266 98

Human lysyl-tRNA synthetase (LysRS) is a tRNA-binding protein that is selectively packaged into HIV-1 along with its cognate tRNALys isoacceptors. Evidence exists that Gag alone is sufficient for the incorporation of LysRS into virions. Herein, using both in vitro and in vivo methods, we begin to map regions in Gag and LysRS that are required for this interaction. In vitro reactions between wild-type and truncated HIV-1 Gag and human LysRS were monitored using GST-tagged molecules and glutathione-agarose chromatography. Gag/LysRS interaction in vivo was detected in 293FT cells cotransfected with plasmids coding for wild-type or mutant HIV-1 Gag and LysRS, either by monitoring Gag.LysRS complexes immunoprecipitated from cell lysate with anti-LysRS or by measuring the ability of LysRS to be packaged into budded Gag viral-like particles. Based on these studies, we conclude that the Gag/LysRS interaction depends upon Gag sequences within the C-terminal domain of capsid (the last 54 amino acids) and amino acids 208-259 of LysRS. The latter domain includes the class II aminoacyl-tRNA synthetase consensus sequence known as motif 1. Both regions have been implicated in homodimerization of capsid and LysRS, respectively. Sequences falling outside these amino acid stretches can be deleted from either molecule without affecting the Gag/LysRS interaction, further supporting the observation that LysRS is incorporated into Gag viral-like particles independent of its ability to bind tRNALys.
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PMID:The interaction between HIV-1 Gag and human lysyl-tRNA synthetase during viral assembly. 1275 46

The anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) is the drug of choice for preventing maternal-fetal HIV transmission during pregnancy. Our aim was to assess the cytotoxic effects of AZT on human placenta in vitro. The mechanisms of AZT-induced effects were investigated using JEG-3 choriocarcinoma cells and primary explant cultures from term and first-trimester human placentas. Cytotoxicity measures included trypan blue exclusion, MTT, and reactive oxygen species (ROS) assays. Apoptosis was measured with an antibody specific to cleaved caspase-3 and by rescue of cells by the general caspase inhibitor Boc-D-FMK. The effect of AZT on the activities of glutathione-S-transferase, beta-glucuronidase, UDP-glucuronosyl transferase, cytochrome P450 (CYP) 1A, and CYP reductase (CYPR) in the placenta was assessed using biochemical assays and immunoblotting. AZT increased ROS levels, decreased cellular proliferation rates, was toxic to mitochondria, and initiated cell death by a caspase-dependent mechanism in the human placenta in vitro. In the absence of serum, the effects of AZT were amplified in all the models used. AZT also increased the amounts of activity of GST, beta-glucuronidase, and CYP1A, whereas UGT and CYPR were decreased. We conclude that AZT causes apoptosis in the placenta and alters metabolizing enzymes in human placental cells. These findings have implications for the safe administration of AZT in pregnancy with respect to the maintenance of integrity of the maternal-fetal barrier.
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PMID:3'-azido-3'-deoxythymidine (AZT) induces apoptosis and alters metabolic enzyme activity in human placenta. 1455 Jul 50

Interferon-tau (IFN-tau), produced by the embryonic trophectoderm, is a member of type I IFNs required for the establishment of pregnancy in the ruminant ungulates. Although this IFN possesses antiviral activity similar to other type I IFNs, the effectiveness of IFN-tau as an antiviral agent has not been well characterized. To investigate possible antiviral effects of ovine IFN-tau (oIFN-tau), oIFN-tau-GST fusion protein was expressed in E. coli BL21, from which the purified protein isolated possessed anti-viral activity. An apathogenic human foamy virus (hFV) was then used to establish a potential recombinant live vector consisting of oIFN-tau cDNA sense (+) or antisense (-) sequence, oIFN-tau(+)/hFV or oIFN-tau(-)/hFV, respectively. Human hematopoietic and other mammalian cell lines that had been transduced with hFV vector consisting of no oIFN-tau, oIFN-tau(+)/hFV or oIFN-tau(-)/hFV construct were cultured initially for 12 days, and three of cell lines were then maintained for up to 90 days. These cells with oIFN-tau expression directed by hFV exhibited the in vitro cytopathic effect minimally. Transduced cell lines that had been cultured for 90 days were subjected to studies on human immunodeficiency virus type-1 (HIV-1) infection, which was measured with infectivity of viral particles resulted from the GFP inserted T-cell tropic HIV SF2 or macrophage tropic HIV SF162: the number of HIV-1 positive cells was reduced by the hFV driven-intra-cellular oIFN-tau expression. Since oIFN-tau/hFV transduced cells exhibited the resistance to HIV-1 infection and/or replication, oIFN-tau could be considered as one of effective antiviral agents against HIV-1. These results suggest that the hFV genome could be an effective recombinant live vector for the expression of a targeted gene in various cell types.
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PMID:A potential live vector, foamy virus, directed intra-cellular expression of ovine interferon-tau exhibited the resistance to HIV infection. 1503 37

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with cancers in immunocompromised populations. Antiviral drugs targeted against lytic viral replication have limited efficacy in these disease settings. EBV infection of peripheral blood mononuclear cells induces growth proliferation and the EBV latency Epstein-Barr virus-encoded nuclear antigen (EBNA)2 transcriptional transactivator (TAT) is essential for this response. EBNA2 targets the cellular DNA-binding protein CBF1 to mimic activated Notch signaling. A 10-aa peptide from the CBF1 interaction domain of EBNA2 was synthesized as a fusion with the protein transduction domain of HIV-1 TAT. The EBNA2-TAT peptide blocked EBNA2-CBF1 interaction in an in vitro GST affinity assay and labeling with fluorescein confirmed that the EBNA2-TAT peptide efficiently entered cultured B cells. Neither EBNA2-TAT, nor a mutant peptide with a 2-aa substitution that was unable to block the EBNA2-CBF1 interaction, significantly affected the growth of non-EBNA2-expressing EBV(-) B cells or Burkitt's lymphoma Akata cells. However, treatment of an EBV-immortalized lymphoblastoid cell line with the EBNA2-TAT peptide stopped cell growth and reduced cell viability. RT-PCR analyses of gene expression in the peptide-treated lymphoblastoid cell line cultures revealed that EBNA2-TAT treatment down-regulated the EBNA2-responsive viral LMP1 and LMP2 genes and cellular CD23, intercellular adhesion molecule 1, BATF, and Cdk1 genes while up-regulating expression of the cyclin-dependent kinase inhibitor p21. EBV-induced outgrowth of B cells from cultured peripheral blood mononuclear cells was also blocked in a dose-responsive manner by the EBNA2-TAT peptide. This study suggests that cell-permeable EBNA2 peptides may have potential as novel anti-EBV therapeutics.
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PMID:Inhibition of Epstein-Barr virus-induced growth proliferation by a nuclear antigen EBNA2-TAT peptide. 1507 Jul 68

The Nef protein plays a major role in vivo in promoting HIV and SIV replication and pathogenesis. In vitro, Nef has been shown to down-regulate cell surface molecules, such as CD4 and MHC-I, alter T cell signaling, and enhance virion infectivity. These effects are attributed to interactions of Nef with cellular proteins. In addition, HIV Nef is incorporated into viral particles, mainly localizing in the virion cores. However, no report has been published to date regarding Nef interactions with virion proteins. By immunoprecipitation, Nef was found to bind to viral enzymes. Using yeast two-hybrid and GST pulldown procedures to find out direct potential partners of Nef, Nef was consistently found to interact with viral integrase (IN). The interaction between Nef and IN was stronger when Nef was present as the viral protease-cleaved isoform. We hypothesize that the interaction of Nef with viral integrase or other virion proteins may explain the presence of Nef in viral cores. In addition, this interaction suggests that Nef may accompany the reverse transcription and the preintegration complexes during the early steps of the infection cycle and potentially affect infectivity during these steps.
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PMID:Interactions of processed Nef (58-206) with virion proteins of HIV type 1. 1515 58


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