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PubMed1992

Current progress towards vaccines for arenavirus-caused diseases.

The arenaviruses are primarily viruses of rodents, but some members of the group cause severe disease (Argentine and Bolivian haemorrhagic fevers and Lassa fever) when transmitted to humans in the specific areas of the world where they are enzootic. Current research of relevance to the provision of vaccines against these diseases, which highlights many of the problems encountered generally in the development of vaccines, is reviewed here. Although one of the classical approaches to vaccine production, the use of inactivated preparations of virus of varying degrees of purity, has produced no results of promise, attenuation of a virulent strain of Junin virus by passage in cultured cells has yielded a vaccine strain currently being tested for efficacy in protecting against Argentine haemorrhagic fever in the human population at risk. The experimental evidence for protection in animal model systems by related, apparently non-pathogenic, viruses and by recombinant vaccinia viruses expressing arenavirus proteins is discussed, together with some of the potential difficulties of these approaches.

Animals↗
PubMed2003

Alpha-dystroglycan can mediate arenavirus infection in the absence of beta-dystroglycan.

Dystroglycan (DG) is a highly versatile cell surface molecule that provides a molecular link between the extracellular matrix (ECM) and the actin-based cytoskeleton. Encoded by a single gene, DG is posttranslationally processed to form alpha-DG, a peripheral protein identified as the cellular receptor for lymphocytic choriomeningitis virus (LCMV) and Lassa fever virus (LFV), and the membrane-spanning subunit beta-DG. The link of beta-DG to the actin-based cytoskeleton and its association with the cellular signal transduction network suggest that it may function as an essential cofactor for the activity of alpha-DG as a virus receptor. To address this issue, we constructed a deletion mutant lacking the cytoplasmic domain of beta-DG and a C-terminal fusion between alpha-DG and the transmembrane domain of PDGF receptor. Both mutants were functional as virus receptors, indicating that beta-DG does not act as a cofactor with alpha-DG for arenavirus binding and entry. These observations are in agreement with the fact that LCMV infection is independent from the structural integrity of the actin-based cytoskeleton and suggest that alpha-DG functions primarily in the attachment of arenaviruses to the cell surface.

Animals↗
PubMed2006

Recovery of an arenavirus entirely from RNA polymerase I/II-driven cDNA.

The prototypic arenavirus lymphocytic choriomeningitis virus has been a primary workhorse of viral immunologists for almost a century, and it has served as an important model for studying basic principles of arenavirus molecular biology. Its negative-stranded bisegmented RNA genome has, however, posed a major obstacle to attempts at manipulating the infectious virus by reverse genetic techniques. Here, we report the recovery of infectious lymphocytic choriomeningitis virus (the immunosuppressive strain clone 13) entirely from cDNA. Intracellular transcription of the short and the long viral genome segment from polymerase (pol) I-driven vectors and coexpression of the minimal viral-transacting factors NP and L from pol II-driven plasmids resulted in the efficient formation of infectious virus with genetic tags in both genome segments. The cDNA-derived viruses behaved identically to wild-type virus in both cell culture and infected mice. Importantly, they caused a chronic infection and suppressed the adaptive immune response to an unrelated third-party virus. This technology provides an important basis for investigating viral determinants of persistent infection and immunosuppression. In addition, our findings demonstrate that pol I/II-based vector systems may represent an efficient alternative strategy for the recovery of cytoplasmic negative-strand RNA viruses from cDNA.

Animals↗
PubMedDate not supplied

Infection and coding strategies of arenaviruses, phleboviruses, and nairoviruses.

The infection and coding strategies of three groups of negative-stranded RNA viruses (arena viruses, phleboviruses, and nairoviruses) that include the etiologic agents of hemorrhagic disease in humans have been studied. Arenaviruses have two viral RNA species. The smaller RNA species (S) codes for the viral nucleoprotein (N protein) and for the viral glycoprotein species (G1 and G2, which are derived from a precursor glycoprotein, GPC). The S RNA has an ambisense arrangement. The proteins are translated from subgenomic mRNA species (viz., N protein from a viral-complementary mRNA and glycoprotein from a viral-sense mRNA). The larger arenavirus RNA species (L) is presumed to code for the viral transcriptase/replicase. Phleboviruses and nairoviruses are members of the Bunyaviridae. They both have three species of viral RNA. Other than the sizes of the viral proteins and the viral RNA species, virtually nothing is known about the coding strategy of nairoviruses. Phleboviruses have an ambisense coding arrangement to their smallest (S) RNA species. This S RNA codes for the viral N protein (translated from a viral-complementary mRNA) and a nonstructural protein (translated from a viral-sense mRNA). The middle-size (M) RNA of phleboviruses codes for a precursor to the viral glycoproteins (translated from a viral-complementary mRNA). The largest viral RNA (L) is presumed to code for the viral transcriptase/replicase.

Animals↗
PubMed2006

Inhibition of the type I interferon response by the nucleoprotein of the prototypic arenavirus lymphocytic choriomeningitis virus.

The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is a formidable battle horse for the study of viral immunology, as well as viral persistence and associated diseases. Investigations with LCMV have uncovered basic mechanisms by which viruses avoid elimination by the host adaptive immune response. In this study we show that LCMV also disables the host innate defense by interfering with beta interferon (IFN-beta) production in response to different stimuli, including infection with Sendai virus and liposome-mediated DNA transfection. Inhibition of IFN production in LCMV-infected cells was caused by an early block in the IFN regulatory factor 3 (IRF-3) activation pathway. This defect was restored in cells cured of LCMV, indicating that one or more LCMV products are responsible for the inhibition of IRF-3 activation. Using expression plasmids encoding individual LCMV proteins, we found that expression of the LCMV nucleoprotein (NP) was sufficient to inhibit both IFN production and nuclear translocation of IRF-3. To our knowledge, this is the first evidence of an IFN-counteracting viral protein in the Arenaviridae family. Inhibition of IFN production by the arenavirus NP is likely to be a determinant of virulence in vivo.

Active Transport, Cell Nucleus↗
PubMed2006

Role of the stable signal peptide of Junín arenavirus envelope glycoprotein in pH-dependent membrane fusion.

The envelope glycoprotein of the arenaviruses (GP-C) is unusual in that the mature complex retains the cleaved, 58-amino-acid signal peptide. Association of this stable signal peptide (SSP) has been shown to be essential for intracellular trafficking and proteolytic maturation of the GP-C complex. We identify here a specific and previously unrecognized role of SSP in pH-dependent membrane fusion. Amino acid substitutions that alter the positive charge at lysine K33 in SSP affect the ability of GP-C to mediate cell-cell fusion and the threshold pH at which membrane fusion is triggered. Based on the presumed location of K33 at or near the luminal domain of SSP, we postulate that SSP interacts with the membrane-proximal or transmembrane regions of the G2 fusion protein. This unique organization of the GP-C complex may suggest novel strategies for intervention in arenavirus infection.

Amino Acid Sequence↗
PubMed1978

Virion RNA species of the arenaviruses Pichinde, Tacaribe, and Tamiami.

The principal RNA species isolated from labeled preparations of the arenavirus Pichinde usually include a large viral RNA species L (apparent molecular weight = 3.2 X 10(6)), and a smaller viral RNA species S (apparent molecular weight = 1.6 X 10(6)). In addition, either little or considerable quantities of 28S rRNA as well as 18S rRNA can also be obtained in virus extracts, depending on the virus stock and growth conditions used to generate virus preparations. Similar RNA species have been identified in RNA extracted from Tacaribe and Tamiami arenavirus preparations. Oligonucleotide fingerprint analyses have confirmed the host ribosomal origin of the 28S and 18S species. Such analyses have also indicated that the Pichinde viral L and S RNA species each contain unique nucleotide sequences. Viral RNA preparations isolated by conventional phenol-sodium dodecyl sulfate extraction often have much of their L and S RNA species in the form of aggregates as visualized by either electron microscopy or oligonucleotide fingerprinting of material recovered from the top of gels (run by using undenatured RNA preparations). Circular and linear RNA forms have also been seen in electron micrographs of undenatured RNA preparations, although denatured viral RNA preparations have yielded mostly linear RNA species with few RNA aggregates or circular forms.

Arenaviridae↗
PubMed1984

Sequencing studies of pichinde arenavirus S RNA indicate a novel coding strategy, an ambisense viral S RNA.

Analyses of the complete sequence of the 1.1 X 10(6)-dalton, small (S) RNA of the arenavirus Pichinde and virus-induced cellular RNA species have revealed that the viral nucleoprotein, N, is coded in a subgenomic, non-polyadenylated, virus-complementary mRNA corresponding to the 3' half of the viral RNA (Auperin et al., Virology 134:208-219, 1984). By contrast, a second S-coded product, presumably the viral glycoprotein precursor (GPC), is coded in a subgenomic, virus-sense mRNA corresponding to the 5' half of the RNA. Between the two genes is a unique RNA sequence that can be arranged in a hairpin configuration and may function as a transcription terminator for both genes. The term ambisense RNA is coined to describe this novel coding strategy of a viral RNA. The unique feature of the strategy is that the presumptive GPC mRNA and its translation product cannot be made until viral RNA replication has commenced. In addition, it allows the two subgenomic mRNA species to be regulated independently from each other or from other viral mRNA species. The implications of this strategy on possible mechanisms for the induction and maintenance of viral persistence, an important attribute of arenavirus infections, are discussed.

Arenaviridae↗
PubMed1987

Site-specific antibodies define a cleavage site conserved among arenavirus GP-C glycoproteins.

Arenaviruses share a common strategy for glycoprotein synthesis and processing in which a mannose-rich precursor glycoprotein, termed GP-C in lymphocytic choriomeningitis virus (LCMV), is posttranslationally processed by oligosaccharide trimming and proteolytic cleavage to yield two structural glycoproteins, GP-1 and GP-2. Mapping the orientation and proteolytic cleavage site(s) in such polyproteins has traditionally required direct protein sequencing of one or more of the cleaved products. This technique requires rigorous purification of the products for sequencing and may be complicated by amino-terminal modifications which interfere with sequence analysis. We used an alternative approach in which synthetic peptides corresponding to sequences bracketing a potential protease cleavage site were used to raise antisera which define the boundaries of the cleaved products. We found that cleavage of LCMV GP-C to yield GP-1 and GP-2 occurs within a 9-amino-acid stretch of GP-C which contains a paired basic amino acid group -Arg-Arg-, corresponding to amino acids 262 to 263 in the LCMV GP-C sequence. By comparison with the predicted amino acid sequences of a second LCMV strain, LCMV-WE, as well as with the deduced amino acid sequences of the New World arenavirus Pichinde and the Old World virus Lassa, we observed similar conservation of paired basic and flanking amino acid sequences among these viruses.

Amino Acid Sequence↗
PubMed1991

Isolation of an arenavirus from a marmoset with callitrichid hepatitis and its serologic association with disease.

Callitrichid hepatitis (CH) is an acute, often fatal viral infection of New World primates from the family Callitrichidae. The etiologic agent of CH is unknown. We report here the isolation of an arenavirus from a common marmoset (Callithrix jacchus) with CH by using in vitro cultures of marmoset hepatocytes and Vero-E6 cells. Enveloped virions 67 to 133 nm in diameter with ribosomelike internal structures were seen in infected cultures. Immunofluorescence and Western immunoblot analysis using CH-specific antisera (principally from animals exposed to CH during zoo outbreaks) revealed three antigens in cells infected with this CH-associated virus (CHV). These antigens had the same electrophoretic mobilities on sodium dodecyl sulfate-polyacrylamide gels as did the nucleocapsid, GP2, and GPC proteins of lymphocytic choriomeningitis virus (LCMV). Monoclonal antibodies specific for these arenavirus proteins also reacted with the three CHV antigens. Conversely, the CH-specific antisera reacted with the nucleocapsid, GP2, and GPC proteins of LCMV. CHV thus appears to be a close antigenic relative of LCMV. The serologic association of CHV with several CH outbreaks implicate it as the etiologic agent of this disease.

Animals↗
PubMed1995

5' termini of Pichinde arenavirus S RNAs and mRNAs contain nontemplated nucleotides.

Primer extension of Pichinde arenavirus purified virion RNA suggests that genomes have at least a single nontemplated base at the 5' end which is a G in all cDNA clones having one such single base. On the other hand, the predominant products of primer extension on total virus-infected-cell RNA are at positions -1 and -2. The primer extension product at position -2 is not represented in virion RNA, and neither of these products is proportionally represented in mRNA. mRNA is predominantly 3 or 4 bases longer than genomes and antigenomes, but primer extension products as long as 7 bases were observed. The sequence of nontemplated bases reported here is unambiguous with respect to the 5'-terminal base and supports the view that there is a sequence preference for a G at the 5' termini of mRNAs. Assessment of our sequence data in the context of the sequences of Tacaribe and lymphocytic choriomeningitis viruses suggests that the mechanism of initiation of arenavirus transcription is fundamentally different from that of members of the families Orthomyxoviridae and Bunyaviridae.

Animals↗
PubMed1998

An arenavirus RING (zinc-binding) protein binds the oncoprotein promyelocyte leukemia protein (PML) and relocates PML nuclear bodies to the cytoplasm.

The promyelocytic leukemia protein (PML) forms nuclear bodies which are altered in some disease conditions. We report that the cytoplasmic RNA virus lymphocytic choriomeningitis virus (LCMV) influences the distribution of PML bodies. In cells infected with LCMV, the Z protein and PML form large bodies primarily in the cytoplasm. Transient transfection studies indicate that Z alone is sufficient to redistribute PML to the cytoplasm and that PML and Z colocalize. Coimmunoprecipitation studies show specific interaction between PML and Z proteins. A similar result was observed with a Z protein from another arenavirus, Lassa virus, suggesting that this is a general feature of the Arenaviridae. Genetically engineered mutations in PML were used to show that the Z protein binds the N-terminal region of PML and does not need the PML RING or the nuclear localization signal to colocalize. The Z protein acts dominantly to overcome the diffuse phenotype observed in several PML mutants. The interaction between PML and Z may influence certain unique characteristics of arenavirus infection.

3T3 Cells↗
PubMed1981

Mechanisms of persistence in arenavirus infections: a brief review.

A characteristic of the arenaviruses is persistent infections in their natural host. Age at infection is an important factor in the establishment of persistence. Infections early in life regularly result in persistence and this appears to be related to the immaturity of the immune system. Persistently infected animals make antibodies to the viral antigens, which indicates that the animals are not tolerant with respect to B cell functions. However, cytotoxic T cells cannot be demonstrated in persistently infected animals, suggesting a defect in effector T cell functions. The mechanisms leading to this defect in cytotoxic T cells have not been resolved. Persistence of arenaviruses in cell cultures is also regularly observed but the molecular basis for survival of the virus and cell in long-term cultures has yet to be clarified.

Animals↗
PubMed1983

An arenavirus isolated from wild-caught rodents (Pramys species) in the Central African Republic.

We isolated nine arenavirus strains from blood and/or tissues of Praomys sp. rodents wild-caught in derived savannah and forest gallery areas of the Central African Republic (CAR). Convalescent serum from either humans or animals infected by Lassa, Mozambique, or lymphocytic choriomeningitis virus cross-reacted with the strains from the CAR. However, monoclonal antibodies to these three viruses gave a profile against the CAR strains suggesting major antigenic differences between each of them and the CAR virus. These data along with the fact that other African arenaviruses have been recovered from Mastomys natalensis and not Praomys suggest that this virus is significantly different from the others.

Africa, Central↗
PubMed1990

The effect of an arenavirus infection on liver morphology and function.

Patients with severe Lassa fever have high serum levels of liver enzymes. Studies of the histology of the liver have shown only minor alterations, seemingly insufficient to account for death. Pichinde virus is an arenavirus which causes severe illness similar to Lassa fever in strain 13 guinea pigs, but does not cause severe illness in man. This can serve as a relatively safe model for studying the pathology and pathophysiology of fatal arenaviral infection. We used this infection to evaluate the effect of arenavirus on liver morphology and function. When guinea pigs were infected with Pichinde virus, all developed severe disease and died within 14 days of infection. The animals lost large amounts of weight. Higher levels of virus were detected in the liver than in serum. Aspartate aminotransferase and alanine aminotransferase were elevated late in the course of the disease; no elevations were seen in gamma glutamyl transpeptidase or bilirubin. Alkaline phosphatase, initially high in these growing animals, was markedly decreased early in infection. Prothrombin time and activated partial thromboplastin time were increased late in the disease, and decreased levels of Factors VIII and IX were seen relatively early. Fatty metamorphosis, indicating problems in lipid processing, occurred by day 11, but necrosis was minor and occurred late. Pichinde virus infection results in significant alterations in the metabolic and synthetic capacities of the hepatocytes early in infection in the absence of significant necrosis.

Alanine Transaminase↗
PubMed1976

Failure to prove arenavirus infection among the small mammals from an endemic area of Korean hemorrhagic nephrosonephritis.

In the light of recent knowledge on a complex of diseases caused by a new group of viruses, arenaviruses, virological studies largely directed toward small field mammals were undertaken during 1973-1974 aiming at etiological clarification of Korean hemorrhagic nephrosonephritis (KHNN). Specimens were collected in an endemic area of KHNN located north to northeast of Seoul. Virus isolation tests with 299 urine specimens and 131 mite pools recovered from small mammals and 14 acute stage sera from typical cases yielded negative results. Complement-fixation (CF) tests failed to detect antibodies against the antigens of Congo, lymphocytic choriomeningitis (LCM), Tacaribe, and Pichinde viruses among 366 small mammal sera. In addition, CF tests of 59 of the above sera against Apoi and Lassa virus antigens were negative. The results do not support the likelihood of an arenavirus being transmitted among Korean small field mammals, the overwhelming majority of which were Apodemus agrarius. A hypothesis that KHNN is caused by a virus of small field mammal origin was not proved within the technical limit of relatively unsophisticated methods employed herein.

Adolescent↗
PubMedDate not supplied

[Lysosomotropic agents inhibit the penetration of arenaviruses into a culture of BHK-21 and Vero cells].

Lysosomotropic agents (NH4Cl, amantadine, chloroquine, monensin) which prevent acidification of intracellular vacuoles, when introduced into the culture medium before or during inoculation of cells (BHK-21, Vero) with arenaviruses inhibit reproduction of these viruses completely or significantly. Mozambique virus proved to be 10 times more sensitive to the effect of lysosomotropic agents than Pichinde and Lassa viruses. Thus, arenaviruses have a pH-dependent stage at the beginning of the reproduction cycle which is indirectly indicative of their penetration into cells by receptor endocytosis.

Adsorption↗
PubMedDate not supplied

[Development and utilization of an immunoenzyme technic to diagnose arenavirus infections].

The possibility of using ELISA for the detection of arenavirus antigens in different organs of infected newborn white mice as well as in the culture fluids of arenavirus-infected cell cultures was demonstrated. The sensitivity of ELISA in antigen detection 100-200 times exceeds that of the CFT, and the time of antigen detection after inoculation of animals or cell cultures is much shorter. The use of ELISA block for the detection and titration of virus-specific antibody also demonstrated high sensitivity of this method as compared with the CFT.

Animals↗