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PubMed2000

Antiviral effect of brassinosteroids against herpes virus and arenaviruses.

A natural brassinosteroid and a series of synthetic derivatives were found to be good inhibitors of herpes simplex virus type 1 (HSV-1) and arenavirus replication in cell culture. The synthetic compounds tested were analogues of the 24(S) ethylbrassinone. Compounds (22 R,23 R,24S)-2alpha, 3alpha,5alpha,22,23-pentahydroxy-stigmastan-6-one and (22R,23R,24S)-3beta-bromo-5alpha,22,23-trihydroxy stigmastan-6-one were cytotoxic at concentrations of 20-40 microM. (22S,23S,24S)-2alpha,3alpha,22,23-tetrahydroxy-5alpha, stigmastan-6-one, (22R,23R,24S)-3beta-acetoxy-22,23-dihydroxy-5alpha-choles tan-6-one, (22S,23S,24S)-3beta-bromo-22,23-dihydroxy-5alpha-cholestan-6 -one and (22S,23S,24S)-3beta-bromo-5alpha,22,23-trihydroxy-stigmastan -6-one were the most active of the series against HSV-1, with selectivity index (SI) values (CC50/EC50) ranging from 10.6 to 16.5. The majority of the compounds were potent inhibitors of arenaviruses, (22S,23S,24S)-3beta-bromo-5alpha,22,23-trihydroxy-stigmastan -6-one being the most active, with SI values of 307.8 and 692.5 for Tacaribe and Junin viruses, respectively. The antiviral activity of brassinosteroid derivatives was not because of direct inactivation; time-of-addition experiments suggested that a late step in HSV-1 multiplication was affected, whereas arenaviruses remained susceptible to the compounds throughout the replicative cycle.

Animals↗
PubMed2000

Arenavirus antibody in rodents indigenous to coastal southern California.

The purpose of this study was to extend our knowledge on the geographic and natural rodent host ranges of New World arenaviruses in California. Sera from 1,094 sigmodontine and 112 murine rodents were tested for antibody against Whitewater Arroyo and Amapari viruses. Antibody was found in 55 (4.6%) of the 1,206 rodents: 4 from northwestern San Diego County, 3 from Los Angeles County, and 48 from Orange County. The antibody-positive rodents included 8 (7.8%) of 103 Neotoma fuscipes, 1 (0.6%) of 180 Neotoma lepida, 1 (3.1%) of 32 Peromyscus boylii, 8 (11.0%) of 73 Peromyscus californicus, 1 (1.2%) of 85 Peromyscus eremicus, 30 (8.5%) of 353 Peromyscus maniculatus, and 6 (2.2%) of 268 Reithrodontomys megalotis. This study provides the first evidence that New World arenaviruses occur in Los Angeles and Orange counties and northwestern San Diego County, and the first evidence that Peromyscus and Reithrodontomys species are naturally infected with New World arenaviruses.

Animals↗
PubMed1995

Molecular phylogeny of Guanarito virus, an emerging arenavirus affecting humans.

The nucleotide sequence of a portion of the nucleocapsid (N) gene of the Guanarito virus prototype strain (INH-95551) has been determined. It was obtained by direct RNA and polymerase chain reaction (PCR) fragment sequencing of the 3' end of the small (S) RNA fragment. A comparison of this 782-nucleotide segment was done with the known homologous gene sequences of five other arenaviruses: Junin, Machupo, Tacaribe, Pichinde, and lymphocytic choriomeningitis (LCM). Phylogenetic analysis of the N gene open reading frame showed that Guanarito virus is genetically distinct from other members of the Arenavirus family, with 32% nucleotide sequence divergence from Junin, 30% from Machupo, 32% from Tacaribe, 41% from Pichinde, and 45% from LCM. Comparison of amino acids encoded by this sequence region indicated a probable antigenic domain (amino acids 55-63) shared among all arenaviruses studied to date. Along with its host restriction and focal distribution, our data support the hypothesis that this virus has been evolving independently in its endemic focus, for some time.

Amino Acid Sequence↗
PubMed1990

Prediction of arenavirus fusion peptides on the basis of computer analysis of envelope protein sequences.

Theoretical search and selection criteria for putative fusion peptides of enveloped viruses are proposed. Arenavirus fusion peptides are predicted on the basis of computer-assisted analysis of amino acid sequences of arenavirus envelope proteins and elements of their secondary and tertiary structure. Accordingly, two regions of GP2 surface protein from 5 viruses of Arenaviridae family have been detected with properties typical of fusion peptides of other enveloped viruses. One region, named peptide IV, located at the N-terminus of the GP2 protein, is followed by the other region or peptide V, more likely candidate for the arenavirus fusion peptide.

Amino Acid Sequence↗
PubMedDate not supplied

Inhibitory effect of selected antiviral compounds on arenavirus replication in vitro.

Several compounds, belonging to different classes of nucleoside analogues and sulfated polysaccharides, were evaluated for their inhibitory effects on the replication of the arenaviruses Junin and Tacaribe in VERO cells. S-Adenosylhomocysteine (AdoHcy) hydrolase inhibitors [i.e. adenosine dialdehyde, carbocyclic 3-deazaadenosine (C-c3 Ado), neplanocin A, 3-deazaneplanocin A, 9-(2,3-dihydroxypropyl)adenine [(S)-DHPA], (RS)-3-adenin-9-yl-hydroxypropanoic acid isobutyl ester [(RS)-AHPA], the 2',3'-dihydroxycyclopentenyl derivatives of adenine (DHCA) and 3-deazaadenine (DHCDA)] inhibited arenavirus replication within the concentration range of 1-10 micrograms/ml, while not being toxic for cell morphology or cellular DNA synthesis at a concentration of 100-400 micrograms/ml. Based on the ratio of the concentrations required to inhibit cell proliferation and virus replication, only (S)-DHPA, DHCA, C-c3 Ado and adenosine dialdehyde could be considered as truly selective inhibitors. Tubercidin, cyclopentenyl cytosine, pyrazofurin and ribavirin also inhibited viral cytopathogenicity at concentrations that were well below the cytotoxic threshold. Carbodine (cyclopentyl cytosine) also proved to be a potent inhibitor of arenavirus replication, but it was not as selective as cyclopentenyl cytosine. Very potent and selective inhibitors were the sulfated polysaccharides dextran sulfate, lambda-carrageenan, fucoidan, heparin and pentosan polysulfate: they inhibited virus replication at a concentration of 0.1-2.8 micrograms/ml, whereas the compounds were not inhibitory to cell growth even at a concentration of 200 micrograms/ml.

Animals↗
PubMed2005

Genetic analysis of heptad-repeat regions in the G2 fusion subunit of the Junín arenavirus envelope glycoprotein.

The G2 fusion subunit of the Junín virus envelope glycoprotein GP-C contains two hydrophobic heptad-repeat regions that are postulated to form a six-helix bundle structure required for the membrane fusion activity of Class I viral fusion proteins. We have investigated the role of these heptad-repeat regions and, specifically, the importance of the putative interhelical a and d position sidechains by using alanine-scanning mutagenesis. All the mutant glycoproteins were expressed and transported to the cell surface. Proteolytic maturation at the subtilisin kexin isozyme-1/site-1-protease (SKI-1/S1P) cleavage site was observed in all but two of the mutants. Among the adequately cleaved mutant glycoproteins, four positions in the N-terminal region (I333, L336, L347 and L350) and two positions in the C-terminal region (R392 and W395) were shown to be important determinants of cell-cell fusion. Taken together, our results indicate that alpha-helical coiled-coil structures are likely critical in promoting arenavirus membrane fusion. These findings support the inclusion of the arenavirus GP-C among the Class I viral fusion proteins and suggest pharmacologic and immunologic strategies for targeting arenavirus infection and hemorrhagic fever.

Amino Acid Sequence↗
PubMed2006

Rescue of the prototypic Arenavirus LCMV entirely from plasmid.

We document a helper-independent reverse genetics system for rescuing infectious arenaviruses from cloned cDNAs. We constructed plasmids containing full-length cDNAs of the antigenomic (ag) L and S segments of the Armstrong (ARM) strain of the prototypic Arenavirus lymphocytic choriomeningitis virus (LCMV) flanked at their 5'- and 3'-termini by the T7 RNA polymerase (T7RP) promoter and ribozyme sequences, respectively. These plasmids directed intracellular synthesis of viral L and S ag RNA species in cells expressing plasmid-supplied T7RP. Co-expression of plasmid-supplied LCMV trans-acting factors, nucleoprotein (NP) and polymerase (L), resulted in replication and expression of L and S ag and genome RNA species, and generation of LCMV infectious progeny termed rT7/LCMV. The recombinant rT7/LCMV was unequivocally identified based on a genetic tag introduced in the recombinant S segment. In addition, rT7/LCMV exhibited growth and biological properties predicted for an ARM-like LCMV. To our knowledge, this is the first documented Arenavirus rescue, as well as of an ambisense negative strand (NS) RNA virus, entirely from cloned cDNAs. Our results extend the use of reverse genetic approaches for DNA-mediated virus rescue to all known virus families with NS RNA genome.

Animals↗
PubMed2006

Receptor use by pathogenic arenaviruses.

The arenavirus family contains several important human pathogens including Lassa fever virus (LASV), lymphocytic choriomeningitis virus (LCMV) and the New World clade B viruses Junin (JUNV) and Machupo (MACV). Previously, alpha-dystroglycan (alpha-DG) was identified as a receptor recognized by LASV and certain strains of LCMV. However, other studies have suggested that alpha-DG is probably not used by the clade B viruses, and the receptor(s) for these pathogens is currently unknown. Using pseudotyped retroviral vectors displaying arenavirus glycoproteins (GPs), we are able to explore the role played by the GP in viral entry in the absence of other viral proteins. By examining the ability of the vectors to transduce DG knockout murine embryonic stem (ES) cells, we have confirmed that LASV has an absolute requirement for alpha-DG in these cells. However, the LCMV GP can still direct substantial entry into murine ES cells in the absence of alpha-DG, even when the GP from the clone 13 variant is used that has previously been reported to be highly dependent on alpha-DG for entry. We also found that neither LASV or LCMV pseudotyped vectors were able to transduce human or murine lymphocytes, presumably due to the glycosylation state of alpha-DG in these cells. In contrast, the JUNV and MACV GPs displayed broad tropism on human, murine and avian cell types, including lymphocytes, and showed no requirement for alpha-DG in murine ES cells. These findings highlight the importance of molecules other than alpha-DG for arenavirus entry. An alternate receptor is present on murine ES cells that can be used by LCMV but not by LASV, and which is not available on human or murine lymphocytes, while a distinct and widely expressed receptor(s) is used by the clade B viruses.

Animals↗
PubMed2006

Arenavirus Z protein as an antiviral target: virus inactivation and protein oligomerization by zinc finger-reactive compounds.

Several disulfide-based and azoic compounds have shown antiviral and virucidal properties against arenaviruses in virus yield-inhibition and inactivation assays, respectively. The most effective virucidal agent, the aromatic disulfide NSC20625, was able to inactivate two strains of the prototype arenavirus species Lymphocytic choriomeningitis virus (LCMV). Inactivated viral particles retained the biological functions of the virion envelope glycoproteins in virus binding and uptake, but were unable to perform viral RNA replication. Furthermore, in inactivated virions, the electrophoretic profile of the Z protein was altered when analysed under non-reducing conditions, whereas the patterns of the proteins NP and GP1 remained unaffected. Treatment of a recombinant LCMV Z protein with the virucidal agents induced unfolding and oligomerization of Z to high-molecular-mass aggregates, probably due to metal-ion ejection and the formation of intermolecular disulfide bonds through the cysteine residues of the Z RING finger. NSC20625 also exhibited antiviral properties in LCMV-infected cells without affecting other cellular RING-motif proteins, such as the promyelocytic leukaemia protein PML. Altogether, the investigations described here illustrate the potential of the Z protein as a promising target for therapy and the prospects of the Z-reactive compounds to prevent arenavirus dissemination.

Animals↗
PubMed1984

Inhibition of mouse peritoneal macrophage DNA synthesis by infection with the arenavirus Pichinde.

Macrophage DNA synthesis and proliferation occur during the development of cell-mediated immunity and in the early nonspecific reaction to infection. Arenaviruses have a predilection for infection of cells of the reticuloendothelial system, and in this study we have examined the effect of the arenavirus Pichinde on macrophage DNA synthesis. We have found that infection of mouse peritoneal macrophages with Pichinde caused a profound dose-dependent inhibition of the DNA synthesis induced by macrophage growth factor-colony stimulating factor. At a multiplicity of inoculum of 5, there is a 75 to 95% inhibition of DNA synthesis. Viable virus is necessary for inhibition since Pichinde inactivated by heat or cobalt irradiation had no effect. Similarly, virus pretreated with an antiserum to Pichinde was without inhibitory effect. Inhibition was demonstrated by measuring DNA synthesis spectrofluorometrically as well as by [3H]thymidine incorporation. The inhibition of DNA synthesis was not associated with any cytopathology. There was no evidence that the inhibition was due to soluble factors, such as prostaglandins or interferon, released by infected cells. These studies demonstrate, for the first time in vitro, a significant alteration in macrophage function caused by infection with an arenavirus. It is possible that inhibition of macrophage proliferation represents a mechanism by which some microorganisms interfere with host resistance.

Animals↗
PubMed2003

Characterization of the genomic promoter of the prototypic arenavirus lymphocytic choriomeningitis virus.

The genome of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) consists of two negative-sense, single-strand RNA segments designated L and S. Arenavirus genomes exhibit high sequence conservation at their 3' ends. All arenavirus genomes examined to date have a conserved terminal sequence element (3'-terminal 20 nucleotides [nt]) thought to be a highly conserved viral promoter. Terminal complementarity between the 5' and 3' ends of the L and S RNAs predicts the formation of a thermodynamically stable panhandle structure that could contribute to the control of RNA synthesis. We investigated these issues by using a transcription- and replication-competent minireplicon system. A series of overlapping deletions spanning the 3'-terminal 20-nt region of an LCMV minigenome (MG) was generated, and the mutant MGs were analyzed for their activity as templates for RNA synthesis by the LCMV polymerase. The minimal LCMV genomic promoter was found to be contained within the 3'-terminal 19 nt. Substitution of C for G at the last 3'-end nucleotide position in the MG resulted in nondetection of RNA transcription or replication, whereas the addition of a C at the 3' end did not have any significant affect on RNA synthesis mediated by the LCMV polymerase. All other mutations introduced within the 3'-terminal 19 nt of the MG resulted in undetectable levels of promoter activity. Deletions and nucleotide substitutions within the MG 5' end that disrupted terminal complementarity abolished chloramphenicol acetyltransferase expression and RNA synthesis mediated by the LCMV polymerase. These findings indicate that both sequence specificity within the 3'-terminal 19 nt and the integrity of the predicted panhandle structure appear to be required for efficient RNA synthesis mediated by the LCMV polymerase.

Animals↗
PubMed2004

The signal peptide of the Junín arenavirus envelope glycoprotein is myristoylated and forms an essential subunit of the mature G1-G2 complex.

Arenaviruses comprise a diverse family of rodent-borne viruses that are responsible for recurring and emerging outbreaks of viral hemorrhagic fevers worldwide. The Junín virus, a member of the New World arenaviruses, is endemic to the pampas grasslands of Argentina and is the etiologic agent of Argentine hemorrhagic fever. In this study, we have analyzed the assembly and function of the Junín virus envelope glycoproteins. The mature envelope glycoprotein complex is proteolytically processed from the GP-C precursor polypeptide and consists of three noncovalently associated subunits, G1, G2, and a stable 58-amino-acid signal peptide. This tripartite organization is found both on virions of the attenuated Candid 1 strain and in cells expressing the pathogenic MC2 strain GP-C gene. Replacement of the Junín virus GP-C signal peptide with that of human CD4 has little effect on glycoprotein assembly while abolishing the ability of the G1-G2 complex to mediate pH-dependent cell-cell fusion. In addition, we demonstrate that the Junín virus GP-C signal peptide subunit is myristoylated at its N-terminal glycine. Alanine substitution for the modified glycine residue in the GP-C signal peptide does not affect formation of the tripartite envelope glycoprotein complex but markedly reduces its membrane fusion activity. In contrast to the classical view that signal peptides act primarily in targeting nascent polypeptides to the endoplasmic reticulum, we suggest that the signal peptide of the arenavirus GP-C may serve additional functions in envelope glycoprotein structure and trafficking.

Amino Acid Sequence↗
PubMed2005

Genetic and biochemical evidence for an oligomeric structure of the functional L polymerase of the prototypic arenavirus lymphocytic choriomeningitis virus.

The arenavirus L protein has the characteristic sequence motifs conserved among the RNA-dependent RNA polymerase L proteins of negative-strand (NS) RNA viruses. Studies based on the use of reverse-genetics approaches have provided direct experimental evidence of the key role played by the arenavirus L protein in viral-RNA synthesis. Sequence alignment shows six conserved domains among L proteins of NS RNA viruses. The proposed polymerase module of L is located within its domain III, which contains highly conserved amino acids within motifs designated A and C. We have examined the role of these conserved residues in the polymerase activity of the L protein of the prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), in vivo using a minigenome rescue assay. We show here that the presence of sequence SDD, a characteristic of motif C of segmented NS RNA viruses, as well as the presence of the highly conserved D residue within motif A of L proteins, is strictly required for the polymerase activity of the LCMV L protein. The strong dominant negative phenotype associated with many of the mutants examined and results from coimmunoprecipitation studies provided genetic and biochemical evidence, respectively, for the requirement of the L-L interaction for the polymerase activity of the LCMV L protein.

Amino Acid Motifs↗
PubMed2005

RNA interference-mediated virus clearance from cells both acutely and chronically infected with the prototypic arenavirus lymphocytic choriomeningitis virus.

Several arenaviruses, including Lassa fever virus, cause severe, often lethal hemorrhagic fever in humans. No licensed vaccines are available in the United States, and currently there is no efficacious therapy to treat this viral infection. Therefore the importance of developing effective antiviral approaches to combat pathogenic arenaviruses is clear. Moreover, the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is an important model for the study of viral persistence and associated diseases, as well as for exploring therapies to treat viral chronic infections. The use of small interfering RNAs (siRNAs) to downregulate gene expression via RNA interference (RNAi) has emerged as a powerful genetic tool for the study of gene function. In addition, the successful use of siRNAs to target a variety of animal viruses has led us to consider RNAi as a potential novel antiviral strategy. We have investigated the use of RNAi therapy against LCMV. Here, we show that siRNAs targeting sequences within the viral L polymerase and Z mRNAs inhibit LCMV multiplication in cultured cells. Unexpectedly, the antiviral efficacy of RNAi-based therapy against LCMV was highly dependent on the method used to deliver effector siRNA molecules. Thus, transfection of chemically synthesized siRNA pools to L and Z was ineffective in preventing virus multiplication. In contrast, targeting of the same viral L and Z gene products with siRNAs produced inside cells using a replication-deficient recombinant adenovirus expression system inhibited LCMV multiplication very efficiently. Notably, transduction with the replication-deficient recombinant adenovirus expression system to Z and L effectively cured persistently LCMV-infected cells, suggesting the feasibility of using RNAi therapy to combat viral chronic infections by riboviruses.

Adenoviridae↗
PubMed1978

Interrelationships among arenaviruses measured by indirect immunofluorescence.

An evaluation of reciprocal indirect immunofluorescent antibody titers for at least one representative of each known arenavirus serotype leads to the conclusion that the Old World aranaviruses are more closely related to each other than to other members of the group. These relationships are particularly evident in evaluations of human convalescent sera. New World arenaviruses cross-react strongly with each other in most instances but only weakly with with Old World arenaviruses.

Animals↗
PubMedDate not supplied

[Study of arenaviruses in the indirect hemagglutination reaction].

The indirect hemagglutination test with erythrocytes sensitized with antibody to LCM and Tacaribe viruses, most typical members of of arenaviruses, has been developed. This test is a sensitive method for detection of arenaviruses in infected materials in vitro. The indirect hemagglutination test and the indirect hemagglutination-inhibition test revealed cross-interaction between LCM and Tacaribe viruses which opens new approaches for group and species identification of arenaviruses.

Hemagglutination Tests↗
PubMed1996

Inhibition of arenavirus multiplication in vitro by phenotiazines.

Trifluoperazine (TFP) and chlorpromazine (CPZ), two pharmacologically active phenotiazine derivatives, were evaluated for their inhibitory activity on the replication of the arenaviruses Junin (JV), the etiological agent of Argentine hemorrhagic fever, Tacaribe virus and Pichinde virus. Both compounds achieved a concentration-dependent inhibition of viral multiplication at concentrations not affecting cell viability. The 50% inhibitory concentration (IC50) values determined by a virus yield inhibition assay for several strains of JV, including a human pathogenic strain, were in the range of 7.7-23.0 microM and the 90% inhibitory concentration (IC90) fluctuated between 16.6 and 35.2 microM. From time of addition and removal experiments, it can be concluded that CPZ inhibited an early stage in the replicative cycle of JV, probably viral entry. TFP also affected JV penetration when present soon after virus adsorption, and also interfered with a later step of viral maturation when added after 7 h of infection. The expression of viral antigens in the cytoplasm of infected cells was highly reduced in the presence of the compounds, as revealed by immunofluorescence staining, whereas no JV proteins were detected at the cell membrane. The distribution pattern of viral proteins was altered in the few cells exhibiting positive fluorescence after treatment with the phenotiazines. The TFP-induced inhibitory effect on JV multiplication was significantly reversed in the presence of 5 microM calmodulin. These data indicate that TFP and CPZ inhibit JV replication in vitro. Our findings suggest that the integrity of the actin microfilaments may be required for optimal arenavirus multiplication.

Animals↗
PubMed1994

New arenavirus isolated in Brazil.

A new arenavirus, called Sabiá, was isolated in Brazil from a fatal case of haemorrhagic fever initially thought to be yellow fever. Antigenic and molecular characterisation indicated that Sabiá virus is a new member of the Tacaribe complex. A laboratory technician working with the agent was also infected and developed a prolonged, non-fatal influenza-like illness. Sabiá virus is yet another arenavirus causing human disease in South America.

Adult↗