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PubMedDate not supplied

Essential viral and cellular zinc and iron containing metalloproteins as targets for novel antiviral and anticancer agents: implications for prevention and therapy of viral diseases and cancer.

In this review the authors summarize the experimental data on the role of a selected group of metalloproteins, particularly viral (v) and cellular (c) zinc finger proteins (ZFP) and iron containing proteins which are involved in cell proliferation, neovascularization, apoptosis, and viral infection. Furthermore, this review summarizes the data embracing the hypothesis that disruption of certain metalloproteins by novel pharmacological agents is a key factor in controlling viral and proliferative diseases. The primary goal of this review is to show the potential therapeutic applications of ZFP disrupting agents, zinc chelators and iron chelators in the control of viral diseases and cancer. It is known that zinc or iron deficiency, resulting from exposure of culture cells to membrane-permeable Zn2+ or Fe(2+)-chelators, can induced apoptosis in virally transformed cells while normal cells remain unaffected under these conditions. Apoptosis is possibly due to simultaneous inactivation of vZFP, cZFP, and/or iron containing proteins, which are essential for maintenance of cellular and viral structure and which are activated in virally transformed cells. New insights concerning apoptosis, viral metalloproteins, and novel antiviral agents will also be reviewed. From the evidence reviewed, one can infer that development of a variety of drugs that control or neutralize vZFP may lead to a new therapeutic approach directed at controlling and preventing a wide spectrum of viral diseases and cancer. Furthermore, the results suggest that these agents may be useful to prevent transmission of viral diseases. Finally, this review not only points out the limits of our understanding of this system, but also directs scientists to opportunities for future research.

Amino Acid Sequence↗

PubMed1978

Studies on cell surface antigens of mouse leukemic and normal lymphocytes. I. Categories of cell surface antigens on mouse leukemia and their serological identification.

Analysis of cell surface antigens is most advanced with mouse tumors, mainly because of the availability of inbred strains with known susceptibility to naturally occuring or induced tumors. The development of serological techniques enables identification of gene products which are expressed on the surface of tumor cells. The naturally occuring and induced leukemias in mice are a particularly suitable model for the studies of surface antigens, because the leukemia cells can be easily obtained in cell suspension, they are highly sensitive to cytotoxic antibodies and they can be compared, because of common origin, with normal thymocytes and lymphocytes. In addition to conventional alloantigens (MHC), differentiation alloantigens (Thy, Tl and Lyt) viral structural (MuLV and occasionally MMTV) also viral related cellular antigens are detectable. Various categories of cell surface antigens and antisera defining their presence on the surface of mouse lymphocyte produced and used for studies carried on in the Department of Tumor Immunology are listed and discussed in the present and following papers (No. I-V).

Animals↗

PubMed2006

Rinderpest virus blocks type I and type II interferon action: role of structural and nonstructural proteins.

Rinderpest virus (RPV) is a paramyxovirus closely related to the human pathogen Measles virus. It causes severe disease in cattle, buffalo, and some wild animals; although it can infect humans, it does not cause disease. Here, we demonstrate that RPV blocks the action of both type I (alpha) and type II (gamma) interferons (IFNs) by blocking the phosphorylation and nuclear translocation of STAT1 and STAT2 and that this block is not related to species specificity. In addition, both wild-type virulent and vaccine strains of the virus blocked IFN action. Unlike the case with some other paramyxoviruses, neither STAT1 nor STAT2 is degraded upon virus infection. STAT1 is bound by both the viral structural protein P, and thereby recruited to concentrations of viral protein in the cell, and the nonstructural protein V. Although both P and V proteins bind to STAT1 and can block IFN action when expressed in transfected cells, the IFN antagonist activity of the P protein is weaker than that of the V protein. The viral C protein also seems to weakly block IFN-induced activation of STAT1 in transfection experiments. However, studies with knockout viruses showed that the viral V protein appears to be the dominant inhibitor of IFN signaling in the context of virus infection, since prevention of viral V expression restored the IFN sensitivity of infected cells. Although a change in the distribution pattern of STAT2 was observed in virus-infected cells, STAT2 was not bound by any viral protein.

Animals↗

PubMed1984

Analysis of proteins, helper dependence, and seroepidemiology of a new human parvovirus.

A new type of defective parvovirus, tentatively designated as adeno-associated virus type 5 (AAV-5), is characterized as far as its proteins, its helper dependence, and its seroepidemiology are concerned. The protein analysis of AAV-5 in polyacrylamide gels demonstrated the presence of three structural polypeptides, corresponding to VP 1, VP 2, and VP 3 of other AAV types. The preparation of monoclonal antibodies against AAV-5 permitted the analysis of viral structural antigen expression by using adenovirus type 12 (Ad 12) or several herpes group viruses as helper viruses, respectively. AAV-5-infected cell cultures coinfected with either Ad 12, Herpes simplex virus (HSV), Cytomegalovirus (CMV), or Varicella Zoster virus (VZV) efficiently synthesize AAV-5 specific antigens. Epstein-Barr virus (EBV) and Herpesvirus saimiri, in contrast, provide only a very weak helper activity for AAV 5 antigen expression. The development of a specific ELISA test permitted screening of human sera for antibodies to AAV-5. Forty-five percent of 926 sera from all age groups and approximately 60% of the adult population reveal antibodies to structural components of this virus. The seroepidemiology differs from that reported for other AAV serotypes. Highest average titers against AAV-5 are observed in the age group between 15 and 20 years. Sera from patients with cervical carcinoma revealed average titers of antibodies well below those of age-matched control groups. Attempts to find higher antibody levels against AAV-5 in specific human diseases failed thus far.

Adolescent↗

PubMed1998

African swine fever virus is wrapped by the endoplasmic reticulum.

African swine fever (ASF) virus is a large DNA virus that shares the striking icosahedral symmetry of iridoviruses and the genomic organization of poxviruses. Both groups of viruses have a complex envelope structure. In this study, the mechanism of formation of the inner envelope of ASF virus was investigated. Examination of thin cryosections by electron microscopy showed two internal membranes in mature intracellular virions and all structural intermediates. These membranes were in continuity with intracellular membrane compartments, suggesting that the virus gained two membranes from intracellular membrane cisternae. Immunogold electron microscopy showed the viral structural protein p17 and resident membrane proteins of the endoplasmic reticulum (ER) within virus assembly sites, virus assembly intermediates, and mature virions. Resident ER proteins were also detected by Western blotting of isolated virions. The data suggested the ASF virus was wrapped by the ER. Analysis of the published sequence of ASF virus (R. J. Yanez et al., Virology 208:249-278, 1995) revealed a reading frame, XP124L, that encoded a protein predicted to translocate into the lumen of the ER. Pulse-chase immunoprecipitation and glycosylation analysis of pXP124L, the product of the XP124L gene, showed that pXP124L was retained in the ER lumen after synthesis. When analyzed by immunogold electron microscopy, pXP124L localized to virus assembly intermediates and fully assembled virions. Western blot analysis detected pXP124L in virions isolated from Percoll gradients. The packaging of pXP124L from the lumen of the ER into the virion is consistent with ASF virus being wrapped by ER cisternae: a mechanism which explains the presence of two membranes in the viral envelope.

African Swine Fever Virus↗

PubMed2000

Antibody responses to respiratory coronavirus infections of cattle during shipping fever pathogenesis.

Antibody responses against respiratory bovine coronavirus (RBCV) infections were monitored in cattle from the onset of a naturally occurring severe shipping fever (SF) epizootic to complete recovery of affected cattle or fatal outcomes. The infection with RBCV was detected in nasal secretions of 86 cattle, and 81 of them developed acute respiratory tract disease, including fatal pneumonia. Cattle nasally shedding RBCV at the beginning of the epizootic experienced characteristic primary immune responses with specific antibodies for hemagglutinin-esterase (HE) and spike (S) glycoproteins. Virus shedding in nasal secretions of the majority of the cattle ceased between days 7 and 14 with the appearance of HE- and S-specific antibodies. Nasal samples and lung tissues from 9 of the 10 fatal cases had high titers of RBCV, but these cattle had only IgM responses to RBCV infections. Cattle remaining negative in RBCV isolation tests entered this epizootic with antibodies against HE and S. Protection against respiratory tract disease was apparently associated with high level of opsonic and virus-neutralizing IgG2. The HE and S glycoproteins were recognized earliest by the bovine immune system while the N protein induced antibody responses during the later stage of initial infection and the early stage of reinfection. The membrane (M) glycoprotein was the least immunogenic of the major viral structural proteins.

Animals↗

PubMed1995

SV40 VP1 assembles into disulfide-linked postpentameric complexes in cell-free lysates.

The simian virus 40 (SV40) capsid is composed of pentameric capsomeres of the major structural protein, Vp1. The chemical nature of Vp1-Vp1 interactions, as well as the role of the minor structural proteins, Vp2 and Vp3, in SV40 assembly is not clear. We show here that Vp1 molecules synthesized in rabbit reticulocyte lysates self-assembled into postpentameric 12S complexes in the absence of other viral structural proteins and in a time and concentration dependent manner. The 12S complexes were resistant to perturbants of noncovalent interactions but were sensitive to reduction by dithiothretiol. Nonreducing SDS-PAGE analysis revealed disulfide-linked VP1 complexes of > 400 kDa. Our results are consistent with crystallography studies of SV40 which suggest involvement of disulfide bonds at a postcapsomeric stage of viral assembly.

Capsid↗

PubMed1996

Demonstration of antibodies to human T-cell lymphotropic virus-I tax in patients with the cutaneous T-cell lymphoma, mycosis fungoides, who are seronegative for antibodies to the structural proteins of the virus.

Although most patients with the cutaneous T-cell lymphoma, mycosis fungoides (MF), are seronegative for human T-cell lymphotropic virus-I or -II (HTLV-I/II) when tested by assays that measure only antibodies to the viral structural proteins, the majority of such patients harbor HTLV-I-related pol and tax proviral sequences that encode proteins not included in routinely used serologic tests. Tax mRNA has also been detected in their peripheral blood mononuclear cells (PBMC). Therefore, it seemed possible that these patients have antibodies to the tax protein. To investigate this, enzyme-linked immunosorbent assays (ELI-SAs) and Western blot assays were set up, using as antigens the full-length HTLV-I tax cloned from the prototypic HTLV-I-infected cell line, C91PL, and from PBMC of a MF patient, as well as a synthetic peptide made to the carboxy-terminal 20 amino acids of tax-I. Of 60 MF patients whose PBMC were shown to be positive for tax proviral DNA and mRNA, 50 (83%) were shown to have tax antibodies. The antigen derived from the MF patient was most useful in detecting such antibodies. These results demonstrate the need for including other HTLV-related antigens in addition to gag and env in serologic tests used to identify HTLV-infected individuals. The findings underscore the fact that individuals considered seronegative on the basis of currently used tests can be infected with HTLV.

Amino Acid Sequence↗

PubMed2001

Nef increases infectivity of HIV via lipid rafts.

Lipid rafts, also known as detergent-resistant membranes (DRM), are microdomains in the plasma membrane enriched in sphingolipids and cholesterol (reviewed in [1, 2]). Human immunodeficiency virus 1 (HIV) buds via lipid rafts [3, 4]. However, the targeting of viral structural components to DRM and its consequences for viral replication are not understood. Moreover, the negative factor Nef from HIV increases viral infectivity (reviewed in [5, 6]). With no apparent differences in structural components and morphology between wild-type and DeltaNef virons, the latter viruses display less efficient reverse transcription in target cells. As Nef is expressed abundantly early in the viral replicative cycle [7], we hypothesized that Nef could affect viral morphogenesis and budding to render viruses more infectious. In this report, we demonstrated first that Nef increases viral budding from lipid rafts. Second, in the presence of Nef, viral envelopes contain more ganglioside (GM1), which is a major component of lipid rafts. This finding correlated directly with the increased infectivity of HIV. Finally, the depletion of exogenous and endogenous cholesterol biochemically and genetically, which disrupted lipid rafts, decreased viral infectivity only in the presence of Nef. Importantly, HIV lacking the nef gene remained unaffected by these manipulations. We conclude that lipids in virions are essential for viral infectivity. Thus, HIV becomes more infectious when it buds from lipid rafts, and Nef plays a major role in this process.

Cholesterol↗

PubMed1989

Intracellular synthesis and processing of the structural glycoproteins of turkey enteric coronavirus.

Pulse labeling of cells with [35S]methionine or [3H]glucosamine at different times after infection, followed by SDS-PAGE and Western immunoblotting analysis using rabbit anti-TCV hyperimmune serum, was used to resolve and identify TCV-induced intracellular proteins. The viral structural proteins (gp 200, gp 140/gp 66, gp 100/gp 120, p 52, and gp 24/p 20) were detected in radiolabeled cell extracts by 9 to 12 hours post-infection, as well as two possible non-structural proteins with apparent mol.wts. of 36,000 and 32,000. The predominant 52,000 nucleocapsid protein could be detected in cell lysates as soon as 6 to 8 hours after infection; it was initially resolved as a complex of 3 closely migrating species with mol.wts. ranging from 46,000 to 52,000. Pulse-chase and immunoprecipitation experiments indicated that gp 200 arose from a putative precursor with mol.wt. of 150,000 to 170,000, that underwent glycosylation. Proteolytic cleavage of gp 200, in turn, probably yielded the gp 100 and gp 120 species. The unique TCV hemagglutinin protein originated from a primary precursor with mol.wt. of 60,000, which underwent rapid dimerization by disulfide bond formation and glycosylation to yield gp 140. The peplomeric and matrix proteins were both shown to be N-glycosylated, as indicated by their sensitivity to tunicamycin (TM) and their resistance to sodium monensin (SM). In the presence of TM, proteins with mol.wts. of 90,000, 120-130,000, and 150,000 accumulated in TCV-infected cells rather than peplomeric glycoproteins, and the matrix protein E1 was only detected in its unglycosylated form. The addition of TM to the culture medium interfered with the maturation of progeny viral particles, as suggested by the absence of peplomers at the surface of the intravacuolar and extracellular virions, and the accumulation of amorphous material not found in the absence of the glycosylation inhibitor. High yields of virus replication were obtained, in the presence of SM, even at concentrations which greatly affected the cellular functions.

Blotting, Western↗

PubMed1995

The packaging phenotype of the SE21Q1b provirus is related to high proviral expression and not trans-acting factors.

The avian packaging cell line SE21Q1b produces particles which encapsidate cellular RNAs. Such RNAs can be reverse transcribed by endogenous polymerase and integrated into the genomes of newly infected cells (M. Linial, Cell 49:93-102, 1987). Genomic RNA is not packaged because the packaging (psi) region of the provirus is deleted. The provirus also lacks the negative-strand primer binding site, which prevents efficient reverse transcription of randomly packaged genomic RNA. Previous work from our laboratory suggested that the trans-acting defect which allows packaging of cellular mRNA mapped to the provirus but did not map to the nucleocapsid region of the gag gene (D.J. Anderson, P. Lee, K. L. Levine, J. Sang, S. A. Shah, O. O. Yang, P. R. Shank, and M. L. Linial, J. Virol. 66:204-216, 1992). We have found, using proviral recombinants between SE21Q1b and wild-type Rous sarcoma virus, that packaging of cellular RNAs does not map to the gag gene. Rather, the propensity of SE21Q1b particles to package cellular mRNA is a function of the high level of particle production in these cells and not of any specific viral structural proteins.

Amino Acid Sequence↗

PubMedDate not supplied

[Synthesis and membrane-dependent processing of a precursor of tick-borne encephalitis virus (flavivirus) structural proteins in cell-free systems].

Conditions that permitted cell-free synthesis of at least one of the non-structural, in addition to two-structural, polypeptides of tick-borne encephalitis virus have been found. The time course of accumulation of virus-specific polypeptides in extracts of Krebs-2 cells and reticulocyte lysates as well as the peptide maps of the products synthesised were studied. A model of generation of viral structural polypeptides has been proposed, according to which a common precursor of these proteins while in a nascent form, is processed in a membrane-dependent reaction into a C-terminal segment, corresponding to the polypeptide moiety of envelope glycoprotein E, and an N-terminal segment, doublet p36/33. Subsequently, an N-terminal segment, corresponding to the core polypeptide C, is cleaved off from p36/33. The remaining C-terminal segment of p36/33 is possibly a precursor of the membrane polypeptide M. The translational strategy of flaviviruses is compared to that of other positive-stranded RNA viruses.

Animals↗

PubMed2005

VaZyMolO: a tool to define and classify modularity in viral proteins.

Viral structural genomic projects aim at unveiling the function of unknown viral proteins by employing high-throughput approaches to determine their 3D structure and to identify their function through fold-homology studies. The 'viral enzyme module localization' (VaZyMolO) tool has been developed, which aims at defining viral protein modules that might be expressed in a soluble and functionally active form, thereby identifying candidates for crystallization studies. VaZyMolO includes 114 complete viral genome sequences of both negative- and positive-sense, single-stranded RNA viruses available from NCBI. In VaZyMolO, a module is defined as a structural and/or functional unit. Modules were first identified by homology search and then validated by the convergence of results from sequence composition analysis, motif search, transmembrane region search and domain definitions, as found in the literature. The public interface of VaZyMolO, which is accessible from http://www.vazymolo.org, allows comparison of a query sequence to all VaZyMolO modules of known function.

DNA, Complementary↗

PubMed1990

Use of monoclonal antibodies in an ELISA for the diagnosis of bovine leukaemia virus infection.

An ELISA diagnostic test for detection of bovine leukaemia virus (BLV) infected animals was developed. The test is based on the use of a mixture of monoclonal antibodies (MAbs) against envelope glycoprotein and against viral structural protein p24. The sensitivity and specificity of the test were found to be dependent on the relative proportions of MAbs of the appropriate epitope specificity. Polystyrene microtitre plates, wells or sticks were firstly coated with a mixture of purified MAbs and then non-purified viral antigens were adsorbed from tissue culture fluid obtained from BLV-producing cells. The optimal conditions for adsorption of MAbs and viral antigens as well as for the ELISA procedure were established. The test is more sensitive and cheaper (no need for virus antigen purification) than the routinely used ELISA using purified virus antigens. The assay is highly specific, rapid, practical and could be easily automated. It is suitable for the detection of BLV-antibodies in blood serum or milk in the large-scale screening programs for BLV-infected animals.

Animals↗

PubMed2004

African swine fever virus structural protein p54 is essential for the recruitment of envelope precursors to assembly sites.

The assembly of African swine fever virus (ASFV) at the cytoplasmic virus factories commences with the formation of precursor membranous structures, which are thought to be collapsed cisternal domains recruited from the surrounding endoplasmic reticulum (ER). This report analyzes the role in virus morphogenesis of the structural protein p54, a 25-kDa polypeptide encoded by the E183L gene that contains a putative transmembrane domain and localizes at the ER-derived envelope precursors. We show that protein p54 behaves in vitro and in infected cells as a type I membrane-anchored protein that forms disulfide-linked homodimers through its unique luminal cysteine. Moreover, p54 is targeted to the ER membranes when it is transiently expressed in transfected cells. Using a lethal conditional recombinant, vE183Li, we also demonstrate that the repression of p54 synthesis arrests virus morphogenesis at a very early stage, even prior to the formation of the precursor membranes. Under restrictive conditions, the virus factories appeared as discrete electron-lucent areas essentially free of viral structures. In contrast, outside the assembly sites, large amounts of aberrant zipper-like structures formed by the unprocessed core polyproteins pp220 and pp62 were produced in close association to ER cisternae. Altogether, these results indicate that the transmembrane structural protein p54 is critical for the recruitment and transformation of the ER membranes into the precursors of the viral envelope.

African Swine Fever Virus↗

PubMed1992

Evidence for zinc binding by two structural proteins of Plodia interpunctella granulosis virus.

Workers in our laboratory previously reported the possibility of cation involvement in the in vitro dissociation of the Plodia interpunctella granulosis virus nucleocapsids (K. A. Tweeten, L. A. Bulla, Jr., and R. A. Consigli, J. Virol. 33:866-876, 1980; M. E. Wilson and R. A. Consigli, Virology 143:516-525, 1985). The current study found zinc associated with both granulosis virus nucleocapsids and granulin by atomic absorption analysis. A blotting assay with 65Zn2+ specifically identified the radioactive cation as binding to two viral structural proteins, granulin and VP12. These findings indicate that zinc may have a critical role in maintaining virus stability.

Amino Acids↗

PubMed1992

Inhibition of human immunodeficiency virus infection in human colon epithelial cells by recombinant interferon-gamma.

Pretreatment of human colon epithelial cells HT29 by recombinant gamma interferon (IFN)-gamma was found to protect the cells from infection with various isolates of human immunodeficiency virus (HIV)-1 and HIV-2, as assessed by co-cultivation with human T lymphoblastoid cells and gene amplification by polymerase chain reaction technique. Additionally, IFN-gamma induced a dose-dependent inhibition of HIV-1 and HIV-2 production in chronically infected HT29 cells. In situ hybridization studies demonstrated that IFN-treated cells were still able to synthesize viral messenger ribonucleic acid. However, the expression of the p24 product of the gag gene was markedly decreased after IFN treatment as demonstrated by radio-immunoprecipitation assay. Taken together, these data suggested that the cytokine acted at the post-translational level by inhibiting the processing of structural viral proteins. It is concluded from this study that IFN-gamma has a potent anti-HIV effect on epithelial gastrointestinal cells.

Cells, Cultured↗

PubMed1989

The primary structure of major viral RNA in a rat cell line transfected with type 47 human papillomavirus DNA and the transforming activity of its cDNA and E6 gene.

A transformed cell line (RC335) showing higher saturation cell density was obtained from 3Y1 cells (a fibroblastic cell line of rat) transfected with DNA of human papillomavirus type 47 (HPV-47), an epidermodysplasia verruciformis-associated virus, which our laboratory reported previously. The cell line was found to produce a major and several minor species of viral RNAs. The primary structure of the major viral RNA in RC335 was extensively studied and found to consist of two exons and contain open reading frames (ORFs) E6, E7, and a fused ORF, E1/E4. The major RNA was indicated to play an important role in the transformation of RC335 by an experiment with the recombinant retrovirus designed to produce the RNA containing these ORFs, i.e., the recombinant virus induced transformation similar to that in RC335 upon infection of 3Y1 cells. Furthermore the experiments with recombinant viruses carrying a nonsense mutation or large deletion in the above ORF(s) indicated that E6 was necessary and sufficient for the transformation.

Animals↗