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)

Efficient entry into, and infection of, human cells by human T-cell leukaemia virus type-1 (HTLV-1) is mediated by the viral envelope glycoproteins, gp46 and gp21. The gp46 surface glycoprotein binds to an as yet unidentified cell surface receptor, thereby, allowing the gp21 transmembrane glycoprotein to initiate fusion of the viral and cellular membranes. In the absence of membrane fusion viral penetration and entry into the host cell cannot occur. The envelope glycoproteins are also a major target for neutralising antibodies and cytotoxic T lymphocytes following a protective immune response, and represent ideal constituents for a recombinant HTLV-1 vaccine. Given the importance of the envelope proteins in HTLV-1 pathogenesis there is increasing interest in obtaining sufficient quantities of these proteins for biochemical, biophysical and biological analyses. We have now developed a system for production of large amounts of a glycosylated and functional form of soluble recombinant gp46 (sRgp46), and have used this recombinant material for analysis of envelope function and receptor binding activity. We find that, the sRgp46 molecules expressed in our system are immunologically indistinguishable from the native virally expressed surface glycoproteins; that sRgp46 binds to T-cells in a dose dependent and saturable manner; and that cell surface binding by sRgp46 can be inhibited by neutralising antibodies. Importantly, we demonstrate that these sRgp46 molecules potently inhibit syncytia formation and viral infection of target cells, and that regions outwith the SU domain of envelope are not required for binding to target cells or for inhibiting membrane fusion. The sRgp46 produced in our study will provide new opportunities to investigate envelope-receptor interactions, and will be of utility in defining the conformationally sensitive antigenic determinants of the HTLV-1 surface glycoprotein.
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PMID:Soluble recombinant HTLV-1 surface glycoprotein competitively inhibits syncytia formation and viral infection of cells. 1152 May 77

Entry of human T-cell leukemia virus type 1 (HTLV-1) into cells is mediated by the viral envelope glycoproteins gp46 and gp21. The gp46 surface glycoprotein binds to a poorly characterized cell surface receptor, thereby promoting the gp21-dependent fusion of the viral and cellular membranes. Interestingly, a synthetic peptide (P-197) simulating amino acids 197 to 216 of gp46 strongly inhibits envelope-dependent membrane fusion with Molt-4 target cells. It has been suggested that this peptide acts by competitively binding to Hsc70, a putative cellular receptor for HTLV-1. We now demonstrate that P-197 inhibits membrane fusion among diverse HTLV-1-permissive target cells. Importantly, most of these cells lack detectable levels of Hsc70, indicating that P-197 inhibits membrane fusion by a mechanism that is Hsc70 independent. We now suggest that competition for primary receptor binding is unlikely to account for the inhibitory activity of P-197. Understanding the mechanism by which P-197 functions may reveal concepts of general relevance to antiretroviral chemotherapy.
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PMID:The synthetic peptide P-197 inhibits human T-cell leukemia virus type 1 envelope-mediated syncytium formation by a mechanism that is independent of Hsc70. 1158 16

Previous studies from our laboratory demonstrated that PVC-211 murine leukemia virus (MuLV), a neuropathogenic variant of Friend MuLV (F-MuLV), had undergone genetic changes which allowed it to efficiently infect rat brain capillary endothelial cells (BCEC) in vivo and in vitro. Two amino acid changes from F-MuLV in the putative receptor binding domain (RBD) of the envelope surface protein of PVC-211 MuLV (Glu-116 to Gly and Glu-129 to Lys) were shown to be sufficient for conferring BCEC tropism on PVC-211 MuLV. Recent examination of the unique RBD of PVC-211 MuLV revealed that the substitution of Lys for Glu at position 129 created a new heparin-binding domain that overlapped a heparin-binding domain common to ecotropic MuLVs. In this study we used heparin-Sepharose columns to demonstrate that PVC-211 MuLV, but not F-MuLV, can bind efficiently to heparin and that one or both of the amino acids in the RBD of PVC-211 MuLV that are associated with BCEC tropism are responsible. We further showed that heparin can enhance or inhibit MuLV infection and that the mode of action is dependent on heparin concentration, sulfation of heparin, and the affinity of the virus for heparin. Our results suggest that the amino acid changes that occurred in the envelope surface protein of PVC-211 MuLV may allow the virus to bind strongly to the surface of BCEC via heparin-like molecules, increasing the probability that the virus will bind to its cell surface receptor and efficiently infect these cells.
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PMID:A unique heparin-binding domain in the envelope protein of the neuropathogenic PVC-211 murine leukemia virus may contribute to its brain capillary endothelial cell tropism. 1171 34

The bone marrow (BM) microenvironment supports leukaemia cell survival and proliferation. The roles played by adhesive receptor interactions in the survival of T-lineage acute lymphoblastic leukaemia (T-ALL) cells on BM stromal cells are not well understood. Recently, we have developed an assay that partially recapitulates the BM microenvironment using HS-5 BM stromal cells. In this assay, the magnitude of ex vivo T-ALL lymphoblast survival predicts patient outcome. We examined the molecular basis for cell-cell adhesive events leading to T-ALL lymphoblast survival on HS-5 and on donor-derived BM stroma. Lympho cyte function-associated antigen-1 (LFA-1) on T-ALL cell lines bound intercellular adhesion molecule-1 (ICAM-1) on HS-5 monolayers, and survival was inhibited 85-98% with monoclonal antibodies directed against LFA-1 or ICAM-1. We compared these results with patient-derived T-ALL lymphoblasts co-cultured on either HS-5 BM or normal BM monolayers and found that LFA-1 and ICAM-1 were required, but not alone sufficient for ex vivo leukaemic cell survival. On normal BM stroma, but not HS-5 monolayers, two additional adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, were highly expressed and contributed to T-ALL cell survival. This is the first report to demonstrate the importance of LFA-1/ICAM-1-mediated adhesion as a critical event in a cascade of cell surface receptor-ligand interactions that regulate T-ALL survival in the BM microenvironment.
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PMID:Enhanced T-lineage acute lymphoblastic leukaemia cell survival on bone marrow stroma requires involvement of LFA-1 and ICAM-1. 1184 20

Pit2 is a type III sodium-dependent phosphate transporter and the cell surface receptor for amphotropic murine leukemia virus. Indirect arguments have previously suggested that retrovirus receptor assembly play a role in triggering membrane fusion. Using CHO cells expressing physiological amounts of functional versions of human Pit2 fused to various tagging epitopes, we provide evidence that Pit2 forms assemblies at the cell surface. Living cells were exposed to cross-linking reagents and protein extracts were treated with trifluoroacetic acid (TFA), a chemical that destroys all protein interactions but covalent links. Assemblies were also detected in the absence of cross-linking and TFA treatment, indicating that they are partially resistant to detergent denaturation. The formation of homo-oligomers was documented by the coimmunoprecipitation of differently tagged molecules. The amounts of Pit2 assemblies detected in the presence or in the absence of cross-linking reagents varied with extracellular inorganic phosphate concentration ([P(i)]). Variation of signal intensity was in the range of twofold, occurred in the absence of de novo protein synthesis and took place at the cell surface. These results indicate that Pit2 assemblies exhibit variable conformations at the surface of living cells. Susceptibility to virus infection and phosphate uptake also vary with extracellular [P(i)]. A model is proposed in which cell surface Pit2 assemblies switch from a compacted to an expanded configuration in response to changes of extracellular [P(i)], and possible relationships with the variation of biological activities are discussed.
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PMID:Pit2 assemblies at the cell surface are modulated by extracellular inorganic phosphate concentration. 1193 96

Envelope glycoproteins (Env) of retroviruses are trimers of SU (surface) and TM (transmembrane) heterodimers and are expressed on virions in fusion-competent forms that are likely to be metastable. Activation of the viral receptor-binding domain (RBD) via its interaction with a cell surface receptor is thought to initiate a cascade of events that lead to refolding of the Env glycoprotein into its stable fusion-active conformation. While the fusion-active conformation of the TM subunit has been described in detail for several retroviruses, little is known about the fusion-competent structure of the retroviral glycoproteins or the molecular events that mediate the transition between the two conformations. By characterizing Env chimeras between the ecotropic and amphotropic murine leukemia virus (MLV) SUs as well as a set of point mutants, we show that alterations of the conformation of the SU glycoprotein strongly elevate Env fusogenicity by disrupting the stability of the Env complex. Compensatory mutations that restored both Env stability and fusion control were also identified, allowing definition of interactions within the Env complex that maintain the stability of the native Env complex. We show that, in the receptor-unbound form, structural interactions between the N terminus of the viral RBD (NTR domain), the proline-rich region (PRR), and the distal part of the C-terminal domain of the SU subunit maintain a conformation of the glycoprotein that is fusion inhibitory. Additionally, we identified mutations that disrupt this fusion-inhibitory conformation and allow fusion activation in the absence of viral receptors, provided that receptor-activated RBD fragments are added in trans during infection. Other mutations were identified that allow fusion activation in the absence of receptors for both the viral glycoprotein and the trans-acting RBD. Finally, we found mutations of the SU that bypass in cis the requirement for the NTR domain in fusion activation. All these different mutations call for a critical role of the PRR in mediating conformational changes of the Env glycoprotein during fusion activation. Our results suggest a model of MLV Env fusion activation in which unlocking of the fusion-inhibitory conformation is initiated by receptor binding of the viral RBD, which, upon disruption of the PRR, allows the NTR domain to promote further events in Env fusion activation. This involves a second type of interaction, in cis or in trans, between the receptor-activated RBD and a median segment of the freed C-terminal domain.
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PMID:Relationship between SU subdomains that regulate the receptor-mediated transition from the native (fusion-inhibited) to the fusion-active conformation of the murine leukemia virus glycoprotein. 1220 46

Infection of T lymphocytes by the cytopathic retrovirus feline leukemia virus subgroup T (FeLV-T) requires FeLIX, a cellular coreceptor that is encoded by an endogenous provirus and closely resembles the receptor-binding domain (RBD) of feline leukemia virus subgroup B (FeLV-B). We determined the structure of FeLV-B RBD, which has FeLIX activity, to a 2.5-A resolution by X-ray crystallography. The structure of the receptor-specific subdomain of this glycoprotein differs dramatically from that of Friend murine leukemia virus (Fr-MLV), which binds a different cell surface receptor. Remarkably, we find that Fr-MLV RBD also activates FeLV-T infection of cells expressing the Fr-MLV receptor and that FeLV-B RBD is a competitive inhibitor of infection under these conditions. These studies suggest that FeLV-T infection relies on the following property of mammalian leukemia virus RBDs: the ability to couple interaction with one of a variety of receptors to the activation of a conserved membrane fusion mechanism. A comparison of the FeLV-B and Fr-MLV RBD structures illustrates how receptor-specific regions are linked to conserved elements critical for postbinding events in virus entry.
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PMID:Structure and mechanism of a coreceptor for infection by a pathogenic feline retrovirus. 1255 12

Mus spicilegus is an Eastern European wild mouse species that has previously been reported to harbor an unusual infectious ecotropic murine leukemia virus (MLV) and proviral envelope genes of a novel MLV subgroup. In the present study, M. spicilegus neonates were inoculated with Moloney ecotropic MLV (MoMLV). All 17 inoculated mice produced infectious ecotropic virus after 8 to 14 weeks, and two unusual phenotypes distinguished the isolates from MoMLV. First, most of the M. spicilegus isolates grew to equal titers on M. dunni and SC-1 cells, although MoMLV does not efficiently infect M. dunni cells. The deduced amino acid sequence of a representative clone differed from MoMLV by insertion of two serine residues within the VRA of SUenv. Modification of a molecular clone of MoMLV by the addition of these serines produced a virus that grows to high titer in M. dunni cells, establishing a role for these two serine residues in host range. A second unusual phenotype was found in only one of the M. spicilegus isolates, Spl574. Spl574 produces large syncytia of multinucleated giant cells in M. dunni cells, but its replication is restricted in other mouse cell lines. Sequencing and mutagenesis demonstrated that syncytium formation could be attributed to a single amino acid substitution within VRA, S82F. Thus, viruses with altered growth properties are selected during growth in M. spicilegus. The mutations associated with the host range and syncytium-inducing variants map to a key region of VRA known to govern interactions with the cell surface receptor, suggesting that the associated phenotypes may result from altered interactions with the unusual ecotropic virus mCAT1 receptor carried by M. dunni.
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PMID:Generation of novel syncytium-inducing and host range variants of ecotropic moloney murine leukemia virus in Mus spicilegus. 1269 9

The E2a-Pbx1 oncoprotein of human pre-B cell leukemia prevents differentiation and maintains continued cell division in cultured myeloid progenitors. Previously, estrogen-dependent forms of E2a-Pbx1 were generated that immortalized neutrophil (ECoM-G cells) or monocyte (ECoM-M cells) progenitors and that permitted their terminal differentiation upon estrogen withdrawal. Here, representational difference analysis (RDA) and Affymetrix array analysis are used to identify changes in gene expression that accompany the early differentiation of these cells. The promoters of these genes, whose expression changes upon E2a-Pbx1 inactivation, integrate the biochemical mechanism through which E2a-Pbx1 arrests differentiation and maintains cell division. Inactivation of E2a-Pbx1 caused the 10- to 80-fold up regulation of a small subset of myeloid differentiation genes (MRP8, Cnlp, NB1, Bactenecin, YM1, Stefin 1, Lipocortin, Lactoferrin, gp91 phox and Ly6-G) and a 10-fold down regulation of the TLE1 corepressor gene, as well as of a group of genes expressed in dividing cells (c-Myc, Nucleophosmin, Spermidine synthase, NOP56, Hnrpa1). Transcription of 97% of cellular genes, including 300 other transcription factor genes (21 Hox genes) and other myeloid genes, varied less than 3-fold, with most varying less than 50%. Therefore, E2a-Pbx1 prevents transcription and maintains the cell cycle by a specific rather than a global transcriptional mechanism. Monocyte progenitors were distinguished by persistent expression of IRF8 and of a category of other genes characterized as "interferon-stimulated" (ISG15, ISG20, Ifit1, Ifi202a, Ifi203, IfiS204, Ifi204-related, IRF7 and Ly6-E.1), as well as by the upregulation of the Lrg21 bZip transcription factor gene during late differentiation. The synchronous expression of stage-specific and cell cycle genes regulated by E2a-Pbx1 in these cell lines comprises a model system in which analysis of their promoters can be used as a starting point to backtrack to the transcriptional mechanisms of oncogenesis by E2a-Pbx1.
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PMID:Transcriptional profiling during the early differentiation of granulocyte and monocyte progenitors controlled by conditional versions of the E2a-Pbx1 oncoprotein. 1291 72

Evidence obtained during the last few years has greatly extended our understanding of the cell surface receptors that mediate infections of retroviruses and has provided many surprising insights. In contrast to other cell surface components such as lectins or proteoglycans that influence infections indirectly by enhancing virus adsorption onto specific cells, the true receptors induce conformational changes in the viral envelope glycoproteins that are essential for infection. One surprise is that all of the cell surface receptors for gamma-retroviruses are proteins that have multiple transmembrane (TM) sequences, compatible with their identification in known instances as transporters for important solutes. In striking contrast, almost all other animal viruses use receptors that exclusively have single TM sequences, with the sole proven exception we know of being the coreceptors used by lentiviruses. This evidence strongly suggests that virus genera have been prevented because of their previous evolutionary adaptations from switching their specificities between single-TM and multi-TM receptors. This evidence also implies that gamma-retroviruses formed by divergent evolution from a common origin millions of years ago and that individual viruses have occasionally jumped between species (zoonoses) while retaining their commitment to using the orthologous receptor of the new host. Another surprise is that many gamma-retroviruses use not just one receptor but pairs of closely related receptors as alternatives. This appears to have enhanced viral survival by severely limiting the likelihood of host escape mutations. All of the receptors used by gamma-retroviruses contain hypervariable regions that are often heavily glycosylated and that control the viral host range properties, consistent with the idea that these sequences are battlegrounds of virus-host coevolution. However, in contrast to previous assumptions, we propose that gamma-retroviruses have become adapted to recognize conserved sites that are important for the receptor's natural function and that the hypervariable sequences have been elaborated by the hosts as defense bulwarks that surround the conserved viral attachment sites. Previously, it was believed that binding to receptors directly triggers a series of conformational changes in the viral envelope glycoproteins that culminate in fusion of the viral and cellular membranes. However, new evidence suggests that gamma-retroviral association with receptors triggers an obligatory interaction or cross-talk between envelope glycoproteins on the viral surface. If this intermediate step is prevented, infection fails. Conversely, in several circumstances this cross-talk can be induced in the absence of a cell surface receptor for the virus, in which case infection can proceed efficiently. This new evidence strongly implies that the role of cell surface receptors in infections of gamma-retroviruses (and perhaps of other enveloped animal viruses) is more complex and interesting than was previously imagined. Recently, another gammaretroviral receptor with multiple transmembrane sequences was cloned. See Prassolov, Y., Zhang, D., Ivanov, D., Lohler, J., Ross, S.R., and Stocking, C. Sodium-dependent myo-inositol transporter 1 is a receptor for Mus cervicolor M813 murine leukemia virus.
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PMID:Cell surface receptors for gammaretroviruses. 1293 75


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