Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined structural interactions between Gag proteins within Moloney murine leukemia virus (M-MuLV) particles by making use of the cysteine-specific cross-linking agents iodine and bis-maleimido hexane. Virion-associated wild-type M-MuLV Pr65Gag proteins in immature particles were intermolecularly cross-linked at cysteines to form Pr65Gag oligomers, from dimers to pentamers or hexamers. Following a systematic approach of cysteine-to-serine mutagenesis, we have shown that cross-linking of Pr65Gag occurred at cysteines of the nucleocapsid (NC) Cys-His motif, suggesting that the Cys-His motifs within virus particles are packed in close proximity. The M-MuLV Pr65Gag protein did not cross-link to the human immunodeficiency virus Pr55Gag protein when the two molecules were coexpressed, indicating either that they did not coassemble or that heterologous Gag proteins were not in close enough proximity to be cross-linked. Using an assembly-competent, protease-minus, cysteine-minus Pr65Gag protein as a template, novel cysteine residues were generated in the M-MuLV capsid domain major homology region (MHR). Cross-linking of proteins containing MHR cysteines showed above-background levels of Gag-Gag dimers but also identified a novel cellular factor, present in virions, that cross-linked to MHR residues. Although the NC cysteine mutation was compatible with M-MuLV particle assembly, deletions of the NC domain were not tolerated. These results suggest that the Cys-His motif is held in close proximity within immature M-MuLV particles by interactions between CA domains and/or non-Cys-His motif domains of the NC.
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PMID:Structural interactions between retroviral Gag proteins examined by cysteine cross-linking. 781 93

Disruption of the vif gene of human immunodeficiency virus (HIV) type 1 affects virus infectivity to various degrees, depending on the T-cell line used. We have concentrated our studies on true phenotypic Vif- mutant particles produced from CEMx174 or H9 cells. In a single round of infection, Vif- virus is approximately 25 (from CEMx174 cells) to 100 (from H9 cells) times less infectious than wild-type virus produced from these cells or than the Vif- mutant produced from HeLa cells. Vif- virions recovered from restrictive cells, but not from permissive cells, are abnormal both in terms of morphology and viral protein content. Notably, they contain much reduced quantities of envelope proteins and altered quantities of Gag and Pol proteins. Although wild-type and Vif- virions from restrictive cells contain similar quantities of viral RNA, no viral DNA synthesis was detectable after acute infection of target cells with phenotypically Vif- virions. To examine the possible role of Vif in viral entry, attempts were made to rescue the Vif- defect in H9 cells by pseudotyping Vif+ and Vif- HIV particles with amphotropic murine leukemia virus envelope. Vif- particles produced in the presence of HIV envelope could not be propagated when pseudotyped. In contrast, when only the murine leukemia virus envelope was present, significant propagation of Vif- HIV particles could be detected. These results demonstrate that Vif is required for proper assembly of the viral particle and for efficient HIV Env-mediated infection of target cells.
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PMID:Human immunodeficiency virus type 1 Vif- mutant particles from restrictive cells: role of Vif in correct particle assembly and infectivity. 788 51

The v-Myb protein encoded by avian myeloblastosis virus causes oncogenic transformation of monoblastic cells committed to the monocyte/macrophage lineage. v-Myb is a doubly truncated form of its normal cellular counterpart, c-Myb. In addition to its N- and C-terminal deletions, v-Myb contains a number of amino acid substitutions relative to c-Myb. We have previously shown that neither overexpression of c-Myb nor introduction of these amino acid substitutions into c-Myb is sufficient for transformation of myelomonocytic cells. However, a doubly truncated form of c-Myb which lacked these substitutions transformed myeloblastic cells that appeared to be committed to the granulocytic pathway. We demonstrate here that mutations in both the DNA-binding and transcriptional activation domains of v-Myb are required for transformation of rapidly growing monoblasts rather than more slowly growing myeloblasts. These rapidly growing monoblasts do not express mim-1, a target gene for the Gag-Myb-Ets protein of E26 leukemia virus, or C/EBP proteins which cooperate with Myb to activate mim-1 expression. Furthermore, v-Myb proteins which contain both sets of these mutations are weaker transcriptional activators relative to proteins which lack these mutations. These results support a model in which amino acid substitutions in v-Myb have been selected for their ability to activate only a subset of those genes which can be activated by a doubly truncated form of c-Myb. In particular, mim-1 appears to represent a class of genes whose expression was selected against during the development of an increasingly virulent strain of avian myeloblastosis virus by passage in animals.
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PMID:Mutations in the DNA-binding and transcriptional activation domains of v-Myb cooperate in transformation. 788 1

We demonstrate a significantly high incidence of human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy (HAM)-or tropical spastic paraparesis (TSP)-like symptoms in WKA rats after injection with HTLV-1-producing MT-2 cells, while no symptoms were observed in F344 rats injected with MT-2 cells or in control WKA rats. Five of the eight (63%) WKA rats injected with MT-2 cells showed HAM/TSP-like paraparesis at 105 weeks of age, but none of seven MT-2-injected F344 rats or eight control WKA rats showed symptoms. This high incidence of HAM/TSP-like symptoms in WKA rats was statistically significant (P < 0.05). Six of the eight (75%) WKA rats injected with MT-2 cells showed HAM/TSP-like paraparesis at 108 weeks of age. HAM/TSP-like symptoms were also observed in one of the two WKA rats injected with HTLV-1-producing Ra-1 cells at 128 weeks of age. HTLV-1 provirus was detected in peripheral blood mononuclear cells in both WKA and F344 rats. The provirus was detected in the spinal cords of the HAM/TSP-like WKA rats that had severe neuropathological changes. WKA and F344 rats showed no significant difference in antibody response against HTLV-1 Gag antigen. However, the antibody response against the C-terminal half of gp46 HTLV-1 envelope protein was lower in WKA rats than in F344 rats. Pathological analysis of the HAM/TSP-like rats showed degeneration of the white matter of the spinal cord and peripheral nerves. These findings suggest that both the genetic background of the host and HTLV-1 infection are important in neuropathogenesis of HAM/TSP-like paraparesis in rats.
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PMID:High incidence of HAM/TSP-like symptoms in WKA rats after administration of human T-cell leukemia virus type 1-producing cells. 793 4

Molecular clones of human T-cell leukemia virus type 1 (HTLV-1) have been constructed and stably propagated in plasmids in Escherichia coli. Expression of Tax could be demonstrated from these clones in fibroblast and epithelial cell lines. HOS cells stably transfected with HTLV-1 clone ACH produced all three classes of viral transcripts and Gag proteins. Virus-like particles were also produced from ACH transfected HOS cells as demonstrated by sucrose gradient and electron microscopic analyses. Transfection of peripheral blood mononuclear cells with ACH resulted in production of infectious virus particles which induced lymphocyte proliferation. This study describes useful reagents for further examination of the biological properties of HTLV-1.
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PMID:Construction and characterization of infectious human T-cell leukemia virus type 1 molecular clones. 794 34

In view of the close similarity between bovine leukemia virus (BLV) and human T-cell leukemia virus type I (HTLV-I) we investigated the possibility of developing specific inhibitors of the proteases of these retroviruses using the purified enzyme from BLV. We tested the ability of this protease to specifically cleave various short oligopeptide substrates containing cleavage sites of BLV and HTLV-I proteases, as well as a recombinant BLV Gag precursor. The best substrate, a synthetic decapeptide bearing the natural cleavage site between the matrix and the capsid proteins of BLV Gag precursor polyprotein, was used to develop an inhibition assay. We determined the relative inhibitory effect of synthetic Gag precursor-like peptides in which the cleavable site was replaced by a non-hydrolyzable moiety. The encouraging inhibitory effect of these compounds indicates that potent non-peptidic inhibitors for retroviral proteases are not unattainable.
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PMID:Inhibition of activity of the protease from bovine leukemia virus. 801 45

Murine AIDS (MAIDS) is characterized by severe lymphadenopathy and splenomegaly. The proliferation of the infected target B cells is also an important manifestation of the disease (M. Huang, C. Simard, D. G. Kay, and P. Jolicoeur, J. Virol. 65:6562-6571, 1991). The etiologic agent of MAIDS is a defective murine leukemia virus that is deleted of most of its pol and env genes and appears to encode a single protein, the Gag precursor Pr60gag protein. Pr60gag is myristylated and attached to the plasma membrane. To study the role myristylation on the function of Pr60gag, we have generated a myristylation-negative (Myr-) mutant of the MAIDS defective virus. We found that Myr- Pr60gag interacted less tightly with the plasma membrane. In addition, the Myr- MAIDS defective virus mutant was unable to induce expansion of infected cells and was nonpathogenic. These results emphasize the essential role of Pr60gag in the disease process. Our data also suggest that Pr60gag, once recruited to the cell membrane through its myristylation, interacts with other membrane-bound effectors to send signals to induce proliferation of the infected cells and to initiate immune dysfunctions.
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PMID:Myristylation of Pr60gag of the murine AIDS-defective virus is required to induce disease and notably for the expansion of its target cells. 805 45

In all retrovirus systems studied, the leader region of the RNA contains a cis-acting sequence called psi that is required for packaging the viral RNA genome. Since the pol and env genes are dispensable for formation of RNA-containing particles, the gag gene product must have an RNA binding domain(s) capable of recognizing psi. To gain information about which portion(s) of Gag is required for RNA packaging in the avian sarcoma and leukemia virus system, we utilized a series of gag deletion mutants that retain the ability to assemble virus-like particles. COS cells were cotransfected with these mutant DNAs plus a tester DNA containing psi, and incorporation of RNA into particles were measured by RNase protection. The efficiency of packaging was determined by normalization of the amount of psi+ RNA to the amount of Gag protein released in virus-like particles. Specificity of packaging was determined by comparisons of psi+ and psi- RNA in particles and in cells. The results indicate that much of the MA domain, much of the p10 domain, half of the CA domain, and the entire PR domain of Gag are unnecessary for efficient packaging. In addition, none of these deleted regions is needed for specific selection of the psi RNA. Deletions within the NC domain, as expected, reduce or eliminate both the efficiency and the specificity of packaging. Among mutants that retain the ability to package, a deletion within the CA domain (which includes the major homology region) is the least efficient. We also examined particles of the well-known packaging mutant SE21Q1b. The data suggest that the random RNA packaging behavior of this mutant is not due to a specific defect but rather is the result of the cumulative effect of many point mutations throughout the gag gene.
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PMID:Efficiency and selectivity of RNA packaging by Rous sarcoma virus Gag deletion mutants. 805 73

Human T cell leukaemia virus type 1 (HTLV-1) protease (PR14) was expressed in bacteria and purified by gel filtration. A continuous spectrophotometric assay was used to measure the kinetic parameters of substrate hydrolysis by PR14. Several peptide substrates containing HTLV-1 sequences known to be cleaved by PR14 were used. Cleavage analysis showed that the affinity with which PR14 binds these substrates is higher than that previously reported for HTLV-1 Gag peptides. Also, the affinities of peptides containing the sites involved in autocleavage of protease from its precursor are higher than for the peptides containing sites required for structural protein maturation. This suggests that the autocatalysis of protease from its own precursor has priority over other cleavage reactions and supports similar observations of an ordered hierarchy of processing events by retroviral proteases. As the N- and C-terminal regions of retroviral aspartic proteases are known to contribute to stability of the dimer by forming antiparallel beta-strands, short peptides corresponding to these terminal sequences of HTLV-1 protease were tested for their ability to inhibit cleavage of substrates by PR14. Inhibition was seen with a C-terminal peptide corresponding exactly to the C-terminal 11 amino acids of the processed PR14, whereas a peptide containing a sequence situated further from the C terminus was less effective. An inhibitor of the protease of human immunodeficiency virus type 1, Ro 31-8959, was found to be a poor inhibitor of PR14.
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PMID:Analysis of substrate cleavage by recombinant protease of human T cell leukaemia virus type 1 reveals preferences and specificity of binding. 807 22

In addition to the Gag-Pol and Env precursors whose translation initiates at AUG codons, murine, feline, and simian type C oncoviruses also express glycosylated Gag-Pol precursors (glycoGag), glycoGag translation is initiated at CUG codons located upstream of the Gag AUG initiation codon. In contrast to Gag, glycoGag is translocated into the endoplasmic reticulum and is absent from virions. Since glycoGag has been described to be dispensable ex vivo, we investigated the in vivo effects of a glycoGag- mutation in the Friend murine leukemia virus (F-MuLV). F-MuLV induces severe early hemolytic anemia and subsequent erythroleukemia within 2 months after inoculation of newborn mice. We obtained a glycoGag- F-MuLV, strain H5, by inserting an octanucleotide linker downstream of the CUG codon leading to the reading of a stop codon in all reading frames upstream of the Gag AUG. F-MuLV H5 did not induce severe early hemolytic anemia, and latency of erythroleukemia was significantly increased most likely because of an approximately 1-week delay in the in vivo spreading. Accordingly, induction of recombinant polytropic viruses was also significantly delayed. Close examination of ex vivo spreading kinetics also showed a slower dissemination of F-MuLV H5. Western blot (immunoblot) performed after inoculation of newborn mice with this glycoGag- virus indicated the emergence of new glycoGag+ viruses. PCR analyses with F-MuLV-specific primers demonstrated in vivo pseudoreversions restoring the glycoGag reading frame. Our results demonstrated that glycoGag expression is positively selected and essential for full spreading and pathogenic abilities.
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PMID:A nonstructural gag-encoded glycoprotein precursor is necessary for efficient spreading and pathogenesis of murine leukemia viruses. 818 23


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