UMLS:C0021051 - FACTA Search

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

The vpr gene product of human immunodeficiency virus type (HIV-1) is a virion-associated regulatory protein. A transferable virion association motif for Vpr is located in the p6 domain of the HIV-1 Gag polyprotein. To map the sequences in p6 that are involved in Vpr incorporation, we analyzed the ability of mutant forms of p6 to direct the incorporation of Vpr into chimeric viral particles. Our results show that the determinants which govern Vpr incorporation are largely confined to a C-terminal region of the p6 domain. Within this region, three hydrophobic residues in a highly conserved sequence motif (L-X-S-L-F-G) are absolutely required. Remarkably, the transfer of the conserved motif and of a single flanking residue to a heterologous Gag polyprotein was sufficient to transfer the ability to incorporate Vpr at moderate levels. The transfer of residues 32 to 46 of p6 led to Vpr incorporation levels that were comparable to those obtained with full-length HIV-1 Gag protein, indicating that this region contains essentially all the information required for efficient Vpr incorporation.
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PMID:A conserved LXXLF sequence is the major determinant in p6gag required for the incorporation of human immunodeficiency virus type 1 Vpr. 852 20

We developed an in vitro binding assay to study the specific interaction between human immunodeficiency virus type 1 (HIV-1) RNA and the Gag polyprotein. Binding of the in vitro-expressed protein to in vitro-transcribed RNA was determined by altered migration of the protein in polyacrylamide gels. We found that a Gag precursor lacking the matrix domain bound specifically to HIV-1 RNA, while deletion of both matrix and capsid domains diminished the specificity of binding. Among several regions of HIV-1 RNA tested, strongest binding was seen with the 5'-most 261 nucleotides, while antisense RNA from the same region did not bind.
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PMID:Specific binding of human immunodeficiency virus type 1 (HIV-1) Gag-derived proteins to a 5' HIV-1 genomic RNA sequence. 852 91

The Vpr protein of human immunodeficiency virus type 1 (HIV-1) is incorporated into the virion by the Gag polyprotein precursor Pr55gag. The importance of the p6gag sequence at the C-terminal end of Pr55gag has a crucial role in Vpr incorporation. To identify the Gag sequences directly involved in Vpr binding, we compared the Vpr binding affinities of the 71 amino acid nucleocapsid protein p7, the C-terminal peptide (35-71) p7C and p6gag by affinity chromatography. p7 and p7C have the strongest Vpr binding activities compared to p6gag. These results suggest that the nucleocapsid protein and its C-terminal domain may be important for the incorporation of Vpr into the mature HIV-1 virion and the subsequent localisation of viral nucleic acid to the cell nucleus by Vpr.
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PMID:The Vpr protein of human immunodeficiency virus type 1 binds to nucleocapsid protein p7 in vitro. 857 60

The human immunodeficiency virus type I (HIV-1) Vpr and HIV-2 Vpx proteins package into virions through interactions with their cognate Gag polyprotein precursor. The targeting properties of Vpr and Vpx have been exploited to incorporate foreign proteins into virions by expression as heterologous fusion molecules (X. Wu, H.-M. Liu, H. Xiao, J. Kim, P. Seshaiah, G. Natsoulis, J. D. Boeke, B. H. Hahn, and J. C. Kappes, J. Virol. 69:3389-3398, 1995). To explore the possibility of utilizing Vpx and Vpr to target dominant negative mutants of the HIV Pol proteins into virions, we fused HIV-2 Vpx with an enzymatically defective protease (PR) mutant. Using a vector system to facilitate transient coexpression with HIV provirus, Vpx-PR-mutant (VpxPR(M)) fusion protein was expressed and packaged efficiently into HIV-2 and simian immunodeficiency virus virions. Immunoblot analysis of purified virions demonstrated that the packaging of VpxPR(M) interfered with the processing of the Gag and Gag/Pol precursor proteins, similar to that of a well-characterized active-site PR inhibitor. The incomplete processing of Gag and Gag/Pol was consistent with a 25-fold reduction in virion infectivity. The coexpression of a packaging defective VpxPR(M) fusion protein with HIV-2 provirus produced virions with fully processed Gag protein, similar to wild-type virions. Importantly, virions trans complemented with a Vpx-chloramphenicol acetyltransferase fusion protein were normal with respect to the processing of Gag protein and the ability to infect and replicate in vitro. These results indicate that VpxPR(M) specifically inhibited the function of the viral protease and provide for the first time proof of principle that the incorporation of foreign proteins into virions via fusion with Vpx can inhibit HIV replication. The use of accessory proteins as vehicles to deliver deleterious proteins to virions, including dominant negative mutants of Pol proteins, may provide new opportunities for application of gene therapy-based antiretroviral strategies. The ability to package PR by expression in trans, independent of the Gag/Pol precursor, also represents a novel approach that may be exploited to study the function of the Pol proteins.
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PMID:Inhibition of human and simian immunodeficiency virus protease function by targeting Vpx-protease-mutant fusion protein into viral particles. 864 68

Cyclophilin A (CyPA) is incorporated into human immunodeficiency virus type 1 (HIV-1) virions via contact with the Gag polyprotein. Genetic or pharmacologic disruption of CyPA incorporation causes a quantitative reduction in virion infectivity with no discernible effects on virion assembly or on endogenous reverse transcriptase activity. Instead, the reduction of virion-associated CyPA is accompanied by a parallel, quantitative decrease in the initiation of viral DNA synthesis after infection of T cells. The infectivity of CyPA-deficient virions is not restored by pseudotyping with Env of amphotropic murine leukemia virus, demonstrating that CyPA is not required for the HIV-1-Env-CD4 interaction. These results indicate that CyPA is required for an early step in the HIV-1 life cycle following receptor binding and membrane fusion but preceding reverse transcription. CyPA is the first cellular protein other than the cell surface receptor shown to be required for an early event in the life cycle of a retrovirus.
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PMID:Cyclophilin A is required for an early step in the life cycle of human immunodeficiency virus type 1 before the initiation of reverse transcription. 864 89

The human immunodeficiency virus type 1 (HIV-1) Gag polyprotein binds to cyclophilin A and incorporates this cellular peptidyl prolyl-isomerase into virions. Disruption of cyclophilin A incorporation, either by gag mutations or by cyclosporine A, inhibits virion infectivity, indicating that cyclophilin A plays an essential role in the HIV-1 life cycle. Using assays for packaging of cyclophilin A into virions and for viral replication sensitivity to cyclosporine A, as well as information gleaned from the alignment of Gag residues encoded by representative viral isolates, we demonstrate that of the five lineages of primate immunodeficiency viruses, only HIV-1 requires cyclophilin A for replication. Cloned viral isolates from clades A, B, and D of HIV-1 group M, as well as a phylogenetically related isolate from chimpanzee, all require cyclophilin A for replication. In contrast, the replication of two outlier (group O) HIV-1 isolates is unaffected by concentrations of cyclosporine A which disrupt cyclophilin A incorporation into virions, indicating that these viruses are capable of replicating independently of cyclophilin A. These studies identify the first phenotypic difference between HIV-1 group M and group O and are consistent with phylogenetic studies suggesting that the two HIV-1 groups were introduced into human populations via separate zoonotic transmission events.
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PMID:Cyclophilin A is required for the replication of group M human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus SIV(CPZ)GAB but not group O HIV-1 or other primate immunodeficiency viruses. 867 42

The cellular peptidyl-prolyl isomerase cyclophilin A (CyPA) is incorporated into human immunodeficiency virus type 1 (HIV-1) virions via direct contacts with the HIV-1 Gag polyprotein. Disruption of the Gag-CyPA interaction leads to the production of HIV-1 particles lacking CyPA; these virions are noninfectious, indicating that contacts between CyPA and Gag are necessary for HIV-1 replication. Here, we have used the yeast two-hybrid system in conjunction with an in vitro binding assay to identify the minimal domain of Gag required for binding to CyPA. Analysis of a panel of gag deletion mutants in the two-hybrid system indicated that a region spanning the central portion of the capsid (CA) domain was sufficient for interactions with CyPA, but discrepancies between results obtained in different fusion protein contexts suggested that multimerization of Gag might also be necessary for binding to CyPA. Consistent with a requirement for multimerization, the binding of Gag to CyPA in vitro required a region within the nucleocapsid (NC) domain shown previously to be important for Gag self-association. Substitution of a heterologous dimerization motif for the region from NC also promoted specific binding to CyPA, confirming that interactions with CyPA are dependent on Gag multimerization. Fusion of the heterologous dimerization motif to a 100-amino-acid domain from CA was sufficient for binding to CyPA in vitro. These results define the minimal CyPA-binding domain within Gag and provide insight into the mechanism by which CyPA is incorporated into HIV-1 virions.
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PMID:Binding of the human immunodeficiency virus type 1 Gag polyprotein to cyclophilin A is mediated by the central region of capsid and requires Gag dimerization. 867 52

Human immunodeficiency virus type 1 (HIV-1) specifically incorporates the host cell peptidyl-prolyl isomerase cyclophilin A into virions via contacts with the capsid (CA) domain of the Gag polyprotein Pr55gag. The immunosuppressant drug cyclosporin A and the nonimmunosuppressive cyclosporin A analog SDZ NIM 811 bind to cyclophilin A and inhibit its incorporation into HIV-1 virions. Both drugs inhibit the virion association of cyclophilin A and the replication of HIV-1 with a similar dose dependence. In contrast, these compounds are inactive against other primate lentiviruses which do not incorporate cyclophilin A, such as simian immunodeficiency virus (SIV). To locate determinants which confer sensitivity to SDZ NIM 811, we generated chimeric proviruses between HIV-1 and SIVmac. A hybrid SIVmac which has the CA-p2 domain of the Gag polyprotein replaced by the corresponding domain from HIV-1 replicated in an established CD4+ cell line and in human but not macaque peripheral blood mononuclear cells. The transfer of the HIV-1 CA-p2 domain to SIVmac led to the efficient incorporation of cyclophilin A, and SDZ NIM 811 effectively inhibited both the virion association of cyclophilin A and the spread of the hybrid virus in infected cultures. We conclude that the HIV-1 CA-p2 domain contains determinants which confer the necessity to interact with cyclophilin A for efficient virus replication. Furthermore, our data show that the CA-p2 domain can play a crucial role in species tropism.
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PMID:The human immunodeficiency virus type 1 capsid p2 domain confers sensitivity to the cyclophilin-binding drug SDZ NIM 811. 870 90

The matrix domain (MA) of the simian immunodeficiency virus (SIV) is encoded by the amino-terminal region of the Gag polyprotein precursor and is the component of the viral capsid that lines the inner surface of the virus envelope. To define domains of the SIV MA protein that are involved in virus morphogenesis, deletion and substitution mutations were introduced in this protein in the context of a gag-protease construct and expressed in the vaccinia virus vector system. The MA mutants were characterized with respect to synthesis and processing of the Gag precursor, assembly and release of virus-like particles, and incorporation of the envelope (Env) glycoprotein into particles. We have identified two regions of the SIV MA which are critical for particle formation. Both domains are located in a central hydrophobic alpha-helix of the SIV MA, according to data on the structure of this protein. In addition, we have characterized a domain whose mutation impairs the incorporation of SIV Env glycoproteins with long transmembrane cytoplasmic tails into particles. Interestingly, these mutant particles retained the ability to associate with SIV Env proteins with short cytoplasmic tails.
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PMID:Identification of domains in the simian immunodeficiency virus matrix protein essential for assembly and envelope glycoprotein incorporation. 870 67

All retroviral nucleocapsid (NC) proteins, except those of spumaretroviruses, contain one or two copies of the conserved sequence motif C-X2-C-X4-H-X4-C. The conserved cysteine and histidine residues coordinate a zinc ion in each such motif. Rice et al. (W. G. Rice, J. G. Supko, L. Malspeis, R. W. Buckheit, Jr., D. Clanton, M. Bu, L. Graham, C. A. Schaeffer, J. A. Turpin, J. Domagala, R. Gogliotti, J. P. Bader, S. M. Halliday, L. Coren, R. C. Sowder II, L. 0. Arthur, and L. E. Henderson, Science 270:1194-1197, 1995) have described a series of compounds which inactivate human immunodeficiency virus type 1 (HIV-1) particles and oxidize the cysteine thiolates in the NC zinc finger. We have characterized the effects of three such compounds on Moloney murine leukemia virus (MuLV). We find that, as with HIV-1, the compounds inactivate cell-free MuLV particles and induce disulfide cross-linking of NC in these particles. The killed MuLV particles were found to be incapable of synthesizing full-length viral DNA upon infection of a new host cell. When MuLV particles are synthesized in the presence of one of these compounds, the normal maturational cleavage of the Gag polyprotein does not occur. The compounds have no effect on the infectivity of human foamy virus, a spumaretrovirus lacking zinc fingers in its NC protein. The resistance of foamy virus supports the hypothesis that the zinc fingers are the targets for inactivation of MuLV and HIV- I by the compounds. The absolute conservation of the zinc finger motif among oncoretroviruses and lentiviruses and the lethality of all known mutations altering the zinc-binding residues suggest that only the normal, wild-type structure can efficiently perform all of its functions. This possibility would make the zinc finger an ideal target for antiretroviral agents.
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PMID:Inactivation of murine leukemia virus by compounds that react with the zinc finger in the viral nucleocapsid protein. 876 2

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