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)

Primary rat hippocampal neurones show pronounced elevations of intracellular calcium within minutes of exposure to the HIV coat protein gp120. Culture of hippocampal neurones with gp120 causes significant neurotoxicity. We find that the peptide VSLSYRCPCRFF, a competitive inhibitor of the CXCR4 chemokine receptor, markedly inhibits toxicity and eliminates the acute calcium elevation. CXCR4 receptors are thought to signal to the Gi/Go family of trimeric GTP binding proteins. Pretreatment of hippocampal neurones with pertussis toxin to inactivate Gi/Go proteins markedly reduced gp120 neurotoxicity. These results indicate that both short and long term effects of gp120 are the result of activation of the CXCR4 receptor.
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PMID:Immediate and neurotoxic effects of HIV protein gp120 act through CXCR4 receptor. 1090 20

The heterosubstituted nucleoside analogue dOTC [( )-2'-deoxy-3'-oxa-4'-thiocytidine, BCH-10652] is a racemic compound structurally related to 3TC (lamivudine), but has the oxygen and sulphur in the furanosyl ring transposed. Both the enantiomers (-)dOTC (BCH-10618) and (+)dOTC (BCH-10619) had equivalent activity against wild-type strains of HIV-1 in C8166 T-cells (EC50 1.0-10.0 microM) and in PBMCs (EC50 0.1-3.0 microM). Investigation of the activity of dOTC and its enantiomers against laboratory strains of HIV-1 with defined resistance to 3TC, AZT (zidovudine), ddl (didanosine), PMEA (adefovir), nevirapine and saquinavir indicated that sensitivity was maintained (<3-fold change in EC50) in all cases, with the exception of HIV-1RF 3TC-resistant viruses. The degree of resistance recorded for dOTC (four- to sevenfold), (-)dOTC (five- to eightfold) and (+)dOTC (five- to >18-fold) against these M1841 or M184V mutants, was significantly less than that recorded for 3TC (>100-fold). In addition, the inhibitory effect of the compounds against clinical isolates of HIV-1 recovered from patients with suspected resistance to 3TC and AZT was investigated. Clinical isolates were genotyped using the Murex Line Probe Assay (LiPA) and subgrouped into wild-type, 3TC-resistant and dual 3TC/AZT-resistant, as well as undefined or mixed genotype populations. Compared with the mean EC50 values obtained with genotypically and phenotypically wild-type clinical isolates, the mean EC50 values calculated for isolates phenotypically resistant to 3TC or 3TC and AZT were only 2.6-, 1.6- and 8.2-fold higher for dOTC, (-)dOTC and (+)dOTC, respectively. When the rate of emergence of virus resistant to dOTC and its enantiomers in vitro was investigated, virus resistant to (+)dOTC was readily selected for (<10 passages), and a methionine (ATG) to isoleucine (ATA) amino acid change at codon 184 was identified. In contrast, virus resistant to dOTC and (-)dOTC took longer to appear (15-20 passages), with a methionine (ATG) to valine (GTG) amino acid change at position 184 identified in both cases. In addition, virus passaged 20 times in the presence of dOTC also had a partial lysine (AAA) to arginine (AGA) exchange at position 65. These viruses showed only low-level resistance to dOTC and its enantiomers, but were highly resistant to 3TC. The antiviral effects of dOTC in combination with the nucleoside RT inhibitors AZT, 3TC, d4T (stavudine) and ddl, the non-nucleoside RT inhibitor nevirapine and the protease inhibitors saquinavir, ritonavir and indinavir was investigated. Two-way drug combination assays were carried out in peripheral blood mononuclear cell (PBMC) cultures by measuring the reduction in p24 viral antigen levels, and data was analysed using the MacSynergy II program. dOTC in combination with 3TC or d4T showed a moderate synergistic effect while all other combinations had an additive interaction.
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PMID:Drug resistance and drug combination features of the human immunodeficiency virus inhibitor, BCH-10652 [(+/-)-2'-deoxy-3'-oxa-4'-thiocytidine, dOTC]. 1095 Mar 91

Members of the interferon-induced class of nuclear factors possess a putative CcN motif, comparable with that within proteins such as the simian virus 40 large tumour antigen (T-ag), which confers phosphorylation-mediated regulation of nuclear-localization sequence (NLS)-dependent nuclear import. Here we examine the functionality of the interferon-induced factor 16 (IFI 16) CcN motif, demonstrating its ability to target a heterologous protein to the nucleus, and to be phosphorylated specifically by the CcN-motif-phosphorylating protein kinase CK2 (CK2). The IFI 16 NLS, however, has novel properties, conferring ATP-dependent nuclear import completely independent of cytosolic factors, as well as binding to nuclear components. The IFI 16 NLS is not recognized with high affinity by the NLS-binding importin heterodimer, and transport mediated by it is insensitive to non-hydrolysable GTP analogues. The IFI 16 NLS thus mediates nuclear import through a pathway completely distinct from that of conventional NLSs, such as that of T-ag, but intriguingly resembling that of the NLS of the HIV-1 transactivator protein Tat. Since the IFI 16 CK2 site enhances nuclear import through facilitating binding to nuclear components, this represents a novel mechanism by which the site regulates nuclear-protein import, and constitutes a difference between the IFI 16 and Tat NLSs that may be of importance in the immune response.
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PMID:Novel properties of the protein kinase CK2-site-regulated nuclear- localization sequence of the interferon-induced nuclear factor IFI 16. 1111

The karyophilic properties of the human immunodeficiency virus, type I (HIV-1) pre-integration complex (PIC) allow the virus to infect non-dividing cells. To better understand the mechanisms responsible for nuclear translocation of the PIC, we investigated nuclear import of HIV-1 integrase (IN), a PIC-associated viral enzyme involved in the integration of the viral genome in the host cell DNA. Accumulation of HIV-1 IN into nuclei of digitonin-permeabilized cells does not result from passive diffusion but rather from an active transport that occurs through the nuclear pore complexes. HIV-1 IN is imported by a saturable mechanism, implying that a limiting cellular factor is responsible for this process. Although IN has been previously proposed to contain classical basic nuclear localization signals, we found that nuclear accumulation of IN does not involve karyopherins alpha, beta1, and beta2-mediated pathways. Neither the non-hydrolyzable GTP analog, guanosine 5'-O-(thiotriphosphate), nor the GTP hydrolysis-deficient Ran mutant, RanQ69L, significantly affects nuclear import of IN, which depends instead on ATP hydrolysis. Therefore these results support the idea that IN import is not mediated by members of the karyopherin beta family. More generally, in vitro nuclear import of IN does not require addition of cytosolic factors, suggesting that cellular factor(s) involved in this active but atypical pathway process probably remain associated with the nuclear compartment or the nuclear pore complexes from permeabilized cells.
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PMID:Characterization of the nuclear import pathway for HIV-1 integrase. 1127 58

Lentivirus envelope glycoproteins have unusually long cytoplasmic domains compared to those of other retroviruses. To identify cellular binding partners of the simian immunodeficiency virus (SIV) envelope transmembrane protein (gp41) cytoplasmic domain (CD), we performed a yeast two-hybrid screen of a phytohemagglutinin-activated human T-cell cDNA library with the SIV gp41 CD. The majority of positive clones (50 of 54) encoded the prenylated Rab acceptor (PRA1). PRA1 is a 21-kDa protein associated with Golgi membranes that binds to prenylated Rab proteins in their GTP-bound state. While the cellular function of PRA1 is presently unknown, this protein appears to participate in intracellular vesicular trafficking, based on its cellular localization and ability to bind multiple members of the Rab protein family. Mammalian two-hybrid assays confirmed the interaction between the SIV gp41 CD and PRA1. Furthermore, gp41 sequences important for PRA1 binding were mapped to a central leucine-rich, amphipathic alpha-helix in the SIV gp41 cytoplasmic tail. Although the human immunodeficiency virus (HIV-1) gp41 CD failed to interact with PRA1 in the yeast two-hybrid system, its interaction with PRA1 was significantly better than that of the SIV gp41 CD in mammalian two-hybrid assays. Interestingly, PRA1 also interacted with the Env CDs of HIV-2, bovine immunodeficiency virus, equine infectious anemia virus, and feline immunodeficiency virus. Thus, PRA1 associates with envelope glycoproteins from widely divergent lentiviruses.
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PMID:Envelope glycoprotein cytoplasmic domains from diverse lentiviruses interact with the prenylated Rab acceptor. 1173 97

The human immunodeficiency virus type 1 (HIV-1) regulatory protein, Rev, mediates the nuclear export of unspliced and singly spliced viral mRNAs by bridging viral RNA and export receptor human CRM1 (hCRM1). Ribonucleoprotein complex formation, including the oligomerization of Rev proteins on viral RNA, must occur to allow export. We show here that Rev-Rev interactions, which are a basis of complex formation, can be initiated without cellular factors and are subsequently enhanced by hCRM1-Ran-GTP. Furthermore, we reveal functions for the Rev carboxy-terminal (C-terminal) region, which is well conserved among many HIV-1 strains, and for which no function has been reported. This region is required for the efficient binding of Rev to hCRM1 and consequently for nuclear export, Rev-Rev dimerization, and full Rev transactivator activity. Consistent with these results, a HIV-1 proviral plasmid that expresses a C-terminally truncated Rev mutant protein produces smaller amounts of the p24 antigen than does a plasmid that possesses an intact rev gene. These results indicate the functional importance of the C-terminal region for full Rev activity, which leads to efficient HIV-1 replication.
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PMID:The carboxy-terminal region of the human immunodeficiency virus type 1 protein Rev has multiple roles in mediating CRM1-related Rev functions. 1213 13

Trichosanthin (TCS), a Type I Ribosome Inactivating Protein isolated from the root tuber of Trichosanthes Kirilowii M. has various biological activities including abortion induction, anti-tumor and anti-HIV. The mechanism of TCS specifically killing sensitive cells has not been studied clearly. In this study, we initially found that there exists TCS-affinity molecule on Syncytiotrophoblast cells and Jar cells. Furthermore, by [35S]GTP gamma S Binding Assay, we find that TCS can activate G protein on the membrane of TCS-sensitive cells. These results indicate that on the membrane of TCS-sensitive cells exists TCS-specific receptor.
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PMID:[Activation of G protein on the membrane of TCS-sensitive cells]. 1254 80

HIV Nef has a number of important biological effects, including the down-modulation of several immunological important molecules (CD4, major histocompatibility complex [MHC] class I). Down-modulation of CD4 seems to be via clathrin-dependent endocytosis, whereas down-modulation of MHC class I remains unexplained. Several mutant proteins, including mutations in the small GTPase Arf6, have been used to probe membrane traffic pathways. One such mutant has recently been used to propose that Nef acts through Arf6 to activate the endocytosis of MHC class I. Here, we show that MHC class I down-modulation is unaffected by other Arf6 mutants that provide more specific perturbations in the GDP-GTP cycling of Arf6. Inhibition of phosphatidylinositol-3-phosphate kinase, an upstream activator of Arf6, also had no effect on the internalization step, but its activity is required to direct MHC class I to the trans-Golgi network. We conclude that the apparent Arf6 dependency of Nef-mediated MHC class I down-modulation is due to nonspecific perturbations in membrane traffic.
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PMID:HIV Nef-mediated major histocompatibility complex class I down-modulation is independent of Arf6 activity. 1461 2

Numerous metabolic and genetic diseases are due to mutations in adaptins, dynamin-like GTP-ases or disorders in trafficking machinery mediated by Rab proteins. A great number of pathogenes including viruses (HIV, SIV), bacteria and protozoa use various elements of endocytic/trafficking machinery to get into the host cells and to make their infection successful. Their different strategies are discussed.
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PMID:[Role of the adaptins, dynamin like GTP-ases and Rab proteins in metabolic disorders and various infections]. 1500 67

Human lens epithelium-derived growth factor (LEDGF)/p75 protein forms a specific nuclear complex with human immunodeficiency virus type 1 (HIV-1) integrase and is essential for nuclear localization and chromosomal association of the viral protein. We now studied nuclear import of LEDGF/p75 in live and semipermeabilized cells. We show that nuclear import of LEDGF/p75 is GTP-, Ran-, importin-alpha/beta-, and energy-dependent and that the protein competes with the canonical SV40 large T antigen nuclear localization signal (NLS) for nuclear import receptors. We identified the NLS of LEDGF/p75 through deletion analysis and site-directed mutagenesis. The LEDGF/p75 NLS, 148GRKRKAEKQ156, belongs to the canonical SV40-like family. Fusion of this short peptide to the amino terminus of Escherichia coli beta-galactosidase rendered the fusion protein nuclear, confirming that the LEDGF/p75 NLS is transferable. Moreover, a single amino acid change in the NLS was sufficient to exclude the mutant LEDGF/p75 protein from the nucleus and abolish nuclear import of HIV-1 integrase.
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PMID:Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75. 1516 64


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