Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) Tat proteins are related transcriptional activators whose effects are likely to be mediated by a cellular factor. Using an in vitro kinase assay, we have shown that the Tat protein of HIV-2 and the activation domain of the Tat protein of HIV-1 specifically bind to a cellular protein kinase. Mutations in Tat that abolish transactivation activity in vivo abrogate the ability of the mutants to bind to the kinase in vitro. This is the first demonstration of a cellular factor that binds to Tat that is specific for a functional activation domain of Tat and that displays a biochemical activity. Additionally, we show that the Tat protein of HIV-2 serves as a substrate of the kinase in vitro. Consistent with the in vitro results, the Tat protein of HIV-2 interacts with a cellular kinase in HIV-2 Tat-transfected cells and is phosphorylated in vivo. These results suggest that a cellular serine/threonine kinase may act as a mediator of Tat function.
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PMID:Specific interaction of the human immunodeficiency virus Tat proteins with a cellular protein kinase. 824 83

In the replication of human immunodeficiency virus type 1 (HIV-1), gag MA (matrix), a major structural protein of the virus, carries out opposing targeting functions. During virus assembly, gag MA is cotranslationally myristoylated, a modification required for membrane targeting of gag polyproteins. During virus infection, however, gag MA, by virtue of a nuclear targeting signal at its N terminus, facilitates the nuclear localization of viral DNA and establishment of the provirus. We now show that phosphorylation of gag MA on tyrosine and serine prior to and during virus infection facilitates its dissociation from the membrane, thus allowing it to translocate to the nucleus. Inhibition of gag MA phosphorylation either on tyrosine or on serine prevents gag MA-mediated nuclear targeting of viral nucleic acids and impairs virus infectivity. The requirement for gag MA phosphorylation in virus infection is underscored by our finding that a serine/threonine kinase is associated with virions of HIV-1. These results reveal a novel level of regulation of primate lentivirus infectivity.
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PMID:Phosphorylation-dependent human immunodeficiency virus type 1 infection and nuclear targeting of viral DNA. 855 40

The nef genes of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) encode a 27- to 34-kDa myristoylated protein which induces downregulation of CD4 surface levels and enhances virus infectivity. In adult macaques, Nef has been implicated in pathogenesis and disease progression. Both HIV-1 SF2 Nef and SIVmac239 Nef have been shown to associate with a cellular serine/threonine kinase. We tested five functional Nef isolates to examine whether this kinase association is a property conserved among different isolates. HIV-1 SF2 and 248 and SIVmac239 Nef proteins were found associated with the kinase. HIV-1 NL4-3 and 233 Nef proteins were found weakly associated or not associated with the kinase. All five Nef isolates efficiently downregulated CD4 cell surface expression, suggesting that the association with this cellular kinase is not required for Nef to downregulate CD4. Comparison of the SF2 and NL4-3 isolates shows a differential ability of Nef to enhance infectivity that suggests a possible correlation between kinase association and enhancement of infectivity.
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PMID:The association of Nef with a cellular serine/threonine kinase and its enhancement of infectivity are viral isolate dependent. 870 88

It is now well established that human immunodeficiency virus type I (HIV-1) Nef contributes substantially to disease pathogenesis by augmenting virus replication and markedly perturbing T-cell function. The effect of Nef on host cell activation could be explained in part by its interaction with specific cellular proteins involved in signal transduction, including at least a member of the src family kinase, Lck, and the serine/threonine kinase, mitogen-activated protein kinase (MAPK). Recombinant Nef directly interacted with purified Lck and MAPK in coprecipitation experiments and binding assays. A proline-rich repeat sequence [(Pxx)4] in Nef occurring between amino acid residues 69 to 78 is highly conserved and bears strong resemblance to a defined consensus sequence identified as an SH3 binding domain present in several proteins which can interact with the SH3 domain of various signalling and cytoskeletal proteins. Binding and coprecipitation assays with short synthetic peptides corresponding to the proline-rich repeat sequence [(Pxx)4] of Nef and the SH2, SH3, or SH2 and SH3 domains of Lck revealed that the interaction between these two proteins is at least in part mediated by the proline repeat sequence of Nef and the SH3 domain of Lck. In addition to direct binding to full-length Nef, MAPK was also shown to bind the same proline repeat motif. Nef protein significantly decreased the in vitro kinase activity of Lck and MAPK. Inhibition of key members of signalling cascades, including those emanating from the T-cell receptor, by the HIV-1 Nef protein undoubtedly alters the ability of the infected T cell to respond to antigens or cytokines, facilitating HIV-1 replication and contributing to HIV-1-induced disease pathogenesis.
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PMID:Human immunodeficiency virus type 1 Nef binds directly to Lck and mitogen-activated protein kinase, inhibiting kinase activity. 879 6

We have analyzed CD4-mediated signaling during the early stages of human immunodeficiency virus type 1 (HIV-1) infection. Binding of purified HIV-1 virions or recombinant HIV-1 glycoprotein gp120 to CD4 receptors resulted in association and tyrosine phosphorylation and activation of tyrosine kinase Lck and serine/threonine kinase Raf-1. The association between Lck and Raf-1 was mediated by stimulation of the CD4 receptors, since it was abolished by preincubation of the virus with soluble CD4 and was not detected in CD4-negative A201 T cells. However, the Lck-Raf-1 association was restored in A201 cells permanently transfected with human CD4 cDNA and stimulated with anti-CD4 antibodies. In addition, a catalytically active Lck was required for the association of Lck and Raf-1. Surprisingly, the CD4-mediated signaling, induced by the HIV-1 binding, did not result in stimulation of the Ras GTP-binding activity or its association with Raf-1, indicating that the signaling pathway generated by the HIV-1 binding is not identical to the classical Ras/Raf-1 pathway. Furthermore, overexpression of activated Raf-1 in Jurkat T cells stimulated the HIV long terminal repeat promoter activity and significantly enhanced HIV-1 replication. This suggests that the Lck-Raf-1 pathway, rapidly stimulated by the binding of HIV-1 or gp120 to CD4 receptors, may play an essential role in the transcriptional activation of the integrated HIV-1 provirus as well as in its pathogenicity.
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PMID:Binding of human immunodeficiency virus type 1 to CD4 induces association of Lck and Raf-1 and activates Raf-1 by a Ras-independent pathway. 888 82

The human immunodeficiency virus type 1 matrix (MA) protein is phosphorylated during virion maturation on its C-terminal tyrosine and on several serine residues. Whereas MA tyrosine phosphorylation facilitates viral nuclear import, the significance of MA serine phosphorylation remains unclear. Here, we report that MA serine but not tyrosine phosphorylation is strongly enhanced by Nef. Mutations that abrogated the membrane association of Nef and its ability to bind a cellular serine/threonine kinase greatly diminished the extent of virion MA serine phosphorylation. Correspondingly, a protein kinase coimmunoprecipitated with Nef could phosphorylate MA on serine in vitro, producing a phosphopeptide pattern reminiscent of that of virion MA. Recombinant p21-activated kinase hPAK65, a recently proposed relative of the Nef-associated kinase, achieved a comparable result. Taken together, these data suggest that MA is a target of the Nef-associated serine kinase.
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PMID:The Nef protein of human immunodeficiency virus type 1 enhances serine phosphorylation of the viral matrix. 915 26

Nef proteins from human immunodeficiency virus type 1 isolate SF2 (HIV-1SF2) and simian immunodeficiency virus isolate mac239 (SIVmac239) have been found to associate with a cellular serine/threonine kinase designated NAK. We have recently shown that the association of Nef with NAK is isolate dependent. To identify the structural basis for Nef-kinase association, several chimeric molecules were constructed between SF2 Nef (binding NAK) and 233 Nef (a primary isolate not binding NAK) and stably expressed in HuT-78 human T cells via retrovirus-mediated gene transfer. The Nef 233/SF2/SF2 chimera in which the N-terminal 37 amino acids of SF2 Nef were replaced by those of 233 Nef showed the same ability as SF2 Nef to bind NAK. The Nef 233/SF2/233 chimera in which the N-terminal 37 amino acids and the C-terminal 72 amino acids of SF2 Nef were replaced by corresponding sequences from 233 Nef completely lost the ability to associate with the kinase activity. Furthermore, replacement of the C-terminal 72 amino acids of 233 Nef with the equivalent SF2 sequence (chimera 233/233/SF2) fully restored kinase association to 233 Nef. These results suggest that (i) the core of Nef is not sufficient for NAK binding, (ii) the C terminus of SF2 Nef contains structural determinants important for association with NAK, and (iii) the failure of 233 Nef to bind NAK is due to a defect in its C terminus. Taking advantage of the C terminus of 233 Nef being nonfunctional and using an infectious clone of HIV-1SF2, we show that association with NAK is not required for Nef-mediated infectivity enhancement. While the strong and reproducible association of some Nef isolates with NAK has been clearly established, the role of NAK in Nef function remains to be fully elucidated.
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PMID:Infectivity enhancement by human immunodeficiency virus type 1 Nef is independent of its association with a cellular serine/threonine kinase. 937 15

Replication of human immunodeficiency virus type 1 (HIV-1) is regulated by a host transcription factor, nuclear factor kappaB (NF-kappaB). NF-kappaB belongs to a group of inducible transcription factors and its activity is regulated by multiple cellular signal transduction pathways, including kinases. These kinases are known to be involved in signal-induced NF-kappaB activation and in the induction of HIV-1 gene expression from latently infected cells. In this study we have examined the effect of a newly developed serine/threonine kinase inhibitor, fasudil hydrochloride (FH), on the replication of HIV-1. Although FH was initially developed as a compound that inhibited a myosin light chain kinase (MLCK) and had been approved for clinical use in the treatment of vasospasm after subarachnoid hemorrhage, this study shows its efficacy in blocking HIV-1 replication in latently infected patients. When FH was added to monocytic cell lines latently infected with HIV-1, U1 and OM10.1, the induction of HIV-1 replication by TNF-alpha was blocked at noncytotoxic doses. The IC50 values of HIV-1 induction by FH were 9.3 and 24 microM for U1 and OM10.1, respectively. Because FH could block TNF-alpha-induced, NF-kappaB-dependent gene expression, as examined by the transient luciferase expression assay, the effect of FH was considered to be due to the blocking of the signal transduction pathway of NF-kappaB activation. Although the in vivo effect of FH in blocking HIV-1 induction is not yet known, these findings indicate the feasibility of clinical use of FH and its derivatives in decreasing viral load to prevent clinical development of acquired immunodeficiency syndrome (AIDS) among HIV-1-infected individuals.
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PMID:Inhibition of human immunodeficiency virus type 1 replication by a bioavailable serine/threonine kinase inhibitor, fasudil hydrochloride. 951 89

The nef gene of the human and simian immunodeficiency viruses (HIV and SIV) is dispensable for viral replication in T-cell lines; however, it is essential for high virus loads and progression to simian AIDS (SAIDS) in SIV-infected adult rhesus macaques. Nef proteins from HIV type 1 (HIV-1), HIV-2, and SIV contain a proline-Xaa-Xaa-proline (PxxP) motif. The region of Nef with this motif is similar to the Src homology region 3 (SH3) ligand domain found in many cell signaling proteins. In virus-infected lymphoid cells, Nef interacts with a cellular serine/threonine kinase, designated Nef-associated kinase (NAK). In this study, analysis of viral clones containing point mutations in the nef gene of the pathogenic clone SIVmac239 revealed that several strictly conserved residues in the PxxP region were essential for Nef-NAK interaction. The results of this analysis of Nef mutations in in vitro kinase assays indicated that the PxxP region in SIV Nef was strikingly similar to the consensus sequence for SH3 ligand domains possessing the minus orientation. To test the significance of the PxxP motif of Nef for viral pathogenesis, each proline was mutated to an alanine to produce the viral clone SIVmac239-P104A/P107A. This clone, expressing Nef that does not associate with NAK, was inoculated into seven juvenile rhesus macaques. In vitro kinase assays were performed on virus recovered from each animal; the ability of Nef to associate with NAK was restored in five of these animals as early as 8 weeks after infection. Analysis of nef genes from these viruses revealed patterns of genotypic reversion in the mutated PxxP motif. These revertant genotypes, which included a second-site suppressor mutation, restored the ability of Nef to interact with NAK. Additionally, the proportion of revertant viruses increased progressively during the course of infection in these animals, and two of these animals developed fatal SAIDS. Taken together, these results demonstrated that in vivo selection for the ability of SIV Nef to associate with NAK was correlated with the induction of SAIDS. Accordingly, these studies implicate a role for the conserved SH3 ligand domain for Nef function in virally induced immunodeficiency.
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PMID:Role of the SH3-ligand domain of simian immunodeficiency virus Nef in interaction with Nef-associated kinase and simian AIDS in rhesus macaques. 962 Oct 42

We have recently demonstrated that human immunodeficiency virus type 1 (HIV-1) Nef is required for enhancing viral infectivity by increasing the efficiency of viral entry in a producer-cell-dependent manner, suggesting the possible involvement of a cellular factor(s) in the enhancement of viral entry. Moreover, it has been reported that a proline-rich (PxxP) motif and an Arg-Arg (RR) motif in HIV-1 Nef bind to the SH3 domain of the Src-family tyrosine kinase Hck and to a serine/threonine kinase, respectively. To address whether these cellular kinase binding motifs, PxxP and RR, could be involved in virus producer-cell-dependent enhancement of viral entry, we constructed two nef mutant proviral clones in which these motifs were mutated. The results show that the HIV-1 Nef PxxP motif, which significantly influenced viral infectivity, and the RR motif, which modestly affected viral infectivity, were both dispensable for enhanced viral entry, thus suggesting that another interaction of Nef with a cellular factor(s) is involved in the efficiency of viral entry.
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PMID:The cellular kinase binding motifs (PxxP and RR) in human immunodeficiency virus type 1 Nef protein are dispensable for producer-cell-dependent enhancement of viral entry. 1032 38


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