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PubMed1998

Variation in the glycoprotein and VP35 genes of Marburg virus strains.

Marburg virus, the prototype of the family Filoviridae, differs genetically, serologically, and morphologically from Ebola viruses. To better define the genetic variation within the species, VP35 and glycoprotein (GP) genes of representative human isolates from four known episodes of Marburg virus hemorrhagic fever were analyzed. The percentage nucleotide differences in the GP gene coding regions of Marburg viruses (0.1-21%) was nearly equal to the percentage amino acid changes (0-23%), while the percentage nucleotide differences in VP35 coding regions (0.3-20.9%) were higher than the percentage amino acid changes (0.9-6.1%), indicating a greater number of nonsynonymous changes occurring in the GP gene. The higher variation in the GP gene and the corresponding protein, especially those changes in the variable middle region of the GP, suggests that the variability may be the result of responses to natural host pressures. Analysis of the GP gene open reading frame shows a nonrandom distribution of nonsynonymous mutations that may indicate positive Darwinian selection is operating within the variable region. A heptad repeat region and an adjoining predicted fusion peptide are found in the C-terminal third of Marburg virus GPs, as has been previously shown for Ebola virus, and are similar to those found in transmembrane glycoproteins of retroviruses, paramyxoviruses, coronaviruses, and influenza viruses. Comparative analyses showed that there are two lineages within the Marburg virus species of filoviruses. The most recent isolate from Kenya (1987) represents a separate genetic lineage within the Marburg virus species (21-23% amino acid difference). However, this lineage likely does not represent a separate Marburg subtype, as the extent of divergence is less than that separating Ebola virus subtypes.

Amino Acid Sequence↗
PubMed2004

Reverse genetics of mononegavirales.

"Reverse genetics" or de novo synthesis of nonsegmented negative-sense RNA viruses (Mononegavirales) from cloned cDNA has become a reliable technique to study this group of medically important viruses. Since the first generation of a negative-sense RNA virus entirely from cDNA in 1994, reverse genetics systems have been established for members of most genera of the Rhabdo-, Paramyxo-, and Filoviridae families. These systems are based on intracellular transcription of viral full-length RNAs and simultaneous expression of viral proteins required to form the typical viral ribonucleoprotein complex (RNP). These systems are powerful tools to study all aspects of the virus life cycle as well as the roles of virus proteins in virus-host interplay and pathogenicity. In addition, recombinant viruses can be designed to have specific properties that make them attractive as biotechnological tools and live vaccines.

Animals↗
PubMed2001

Ebola virus: the search for vaccines and treatments.

Ebola viruses belong to the family Filoviridae, which are among the most virulent infectious agents known. These viruses cause acute, and frequently fatal, hemorrhagic fever in humans and nonhuman primates. Currently, no vaccines or treatments are available for human use. This review describes Ebola viruses, with a particular focus on the status of research efforts to develop vaccines and therapeutics and to identify the immune mechanisms of protection.

Animals↗
PubMed1996

Large, virus-like sinuous tubules in the endoplasmic reticulum of human neurons: report from a case of encephalopathy and brief critical review.

We report a case of a rapidly progressive, fatal non-inflammatory demyelinating disease, distinct from multiple sclerosis and lysosomal disorders, in a patient with progressive dementia. Electron microscopy of stereotactic brain biopsy samples revealed the presence in neurons of sinuous, double-walled cylindrical membranous structures within the cisterns of the endoplasmic reticulum. These structures were 75-80 nm in overall diameter, up to 1.5 mm long and had a 40- to 45-nm diameter core. The possibility that they might be viruses of the Filoviridae or Paramyxoviridae families was considered, but the inclusions differed in key morphological aspects from members of both virus families and there were no supporting clinical or pathological data. Neither was it possible to assign the structures to any other known virus family on the basis of their morphology. Such inclusions have been the subject of only three published reports over the past 20 years. Evidence suggests that they may be confined to human central nervous system neurons, but occur in unrelated disorders (Alzheimer's disease, amyotrophic lateral sclerosis, meningoencephalitis, low-pressure hydrocephalus, demyelination). The possibility that they are formed in certain neurons by an abnormal internal budding process, as a response to a variety of pathological insults, is considered most likely, although an infectious origin (such as an unrecognised virus with variable clinical effect) cannot be ruled out.

Adult↗
PubMedDate not supplied

Arbovirus infections and viral haemorrhagic fevers in Uganda: a serological survey in Karamoja district, 1984.

Sera collected in May 1984 from 132 adult residents of Karamoja district, Uganda, were examined by haemagglutination inhibition tests for antibodies against selected arboviruses, namely Chikungunya and Semliki Forest alphaviruses (Togaviridae); dengue type 2, Wesselsbron, West Nile, yellow fever and Zika flaviviruses (Flaviviridae); Bunyamwera, Ilesha and Tahyna bunyaviruses (Bunyaviridae); and Sicilian sandfly fever phlebovirus (Bunyaviridae); and by immunofluorescence tests against certain haemorrhagic fever viruses, Lassa fever arenavirus (Arenaviridae), Ebola-Sudan, Ebola-Zaïre and Marburg filoviruses (Filoviridae), Crimean-Congo haemorrhagic fever nairovirus and Rift Valley fever phlebovirus (Bunyaviridae). Antibodies against Chikungunya virus were the most prevalent (47%), followed by flavivirus antibodies (16%), which were probably due mainly to West Nile virus. No evidence of yellow fever or dengue virus circulation was observed. A few individuals had antibodies against Crimean-Congo haemorrhagic fever, Lassa, Ebola and Marburg viruses, suggesting that these viruses all circulate in the area.

Adult↗
PubMedDate not supplied

Antibodies to haemorrhagic fever viruses in Madagascar populations.

Sera of 381 adult people from 5 areas in Madagascar were tested by the indirect immunofluorescence method for antibodies against Congo-Crimean haemorrhagic fever and Rift Valley fever viruses (Bunyaviridae), Ebola (strains Zaire and Sudan) and Marburg viruses (Filoviridae), and Lassa virus (Arenaviridae). The highest prevalence rate was that of Ebola virus (4.5%). As no haemorrhagic syndrome has been found associated with this virus, the possible presence of a less pathogenic, antigenically related, strain is discussed. The prevalences of Congo-Crimean haemorrhagic fever and Rift Valley viruses were very low, despite previous viral isolations from potential vectors. No serum reacted against Lassa or Marburg antigens. The results are analysed in the light of the geographical and bioecological characteristics of Madagascar, which is a true 'microcontinent' very different from the African mainland.

Adult↗
PubMed1992

Marburg virus, a filovirus: messenger RNAs, gene order, and regulatory elements of the replication cycle.

The genome of Marburg virus (MBG), a filovirus, is 19.1 kb in length and thus the largest one found with negative-strand RNA viruses. The gene order - 3' untranslated region-NP-VP35-VP40-GP-VP30-VP24-L-5' untranslated region-resembles that of other non-segmented negative-strand (NNS) RNA viruses. Six species of polyadenylated subgenomic RNAs, isolated from MBG-infected cells, are complementary to the negative-strand RNA genome. They can be translated in vitro into the known structural proteins NP, GP (non-glycosylated form), VP40, VP35, VP30 and VP24. At the gene boundaries conserved transcriptional start (3'-NNCUNCNUNUAAUU-5') and stop signals (3'-UAAUUCUUUUU-5') are located containing the highly conserved pentamer 3'-UAAUU-5'. Comparison with other NNS RNA viruses shows conservation primarily in the termination signals, whereas the start signals are more variable. The intergenic regions vary in length and nucleotide composition. All genes have relatively long 3' and 5' end non-coding regions. The putative 3' and 5' leader RNA sequences of the MBG genome resemble those of other NNS RNA viruses in length, conservation at the 3' and 5' ends, and in being complementary at their extremities. The data support the concept of a common taxonomic order Mononegavirales comprising the Filoviridae, Paramyxoviridae, and Rhabdoviridae families.

Base Sequence↗
PubMed2006

Viral hemorrhagic fevers.

A taxonomically diverse set of single-stranded ribonucleic acid(ssRNA) viruses from four diverse viral families Arenaviridae,Bunyaviridae, Filoviridae, and Flaviviridae cause an acute systemic febrile syndrome called viral hemorrhagic fever (VHF). The syndrome produces combinations of prostration, malaise, increased vascular permeability, and coagulation maladies. In severe illness,VHF may include generalized bleeding but the bleeding does not typically constitute a life-threatening loss of blood volume. To a certain extent, it is a sign of damage to the vascular endothelium and is an indicator of disease severity in specific target organs. Although the viruses that cause hemorrhagic fever (HF) can productively replicate in endothelial cells, much of the disease pathology including impairment to the vascular system is thought to result primarily from the release of a variety of mediators from virus-infected cells, such as monocytes and macrophages that subsequently alter vascular function and trigger the coagulation disorders that epitomize these infections. While significant progress has been made over the last several years in dissecting out the molecular biology and pathogenesis of the HF viruses, there are currently no vaccines or drugs licensed available for most of the VHFs.

Animals↗
PubMed2004

Other viral bioweapons: Ebola and Marburg hemorrhagic fever.

The term viral hemorrhagic fever refers to a clinical syndrome characterized by acute onset of fever accompanied by nonspecific findings of malaise, prostration, diarrhea,and headache. Patients frequently show signs of increased vascular permeability, and many develop bleeding diatheses. The hemorrhagic fever viruses represent potential agents for biologic warfare because of capability of aerosol transmission, high morbidity,and mortality associated with infection, and ability to replicate in cell culture in high concentrations. Herein we discuss the Filoviridae, the agents of Ebola and Marburg hemorrhagic fevers.

Biological Warfare↗
PubMed2005

Virus-like particles exhibit potential as a pan-filovirus vaccine for both Ebola and Marburg viral infections.

A safe and effective pan-filovirus vaccine is highly desirable since the filoviruses Ebola virus (EBOV) and Marburg virus (MARV) cause highly lethal disease typified by unimpeded viral replication and severe hemorrhagic fever. Previously, we showed that expression of the homologous glycoprotein (GP) and matrix protein VP40 from a single filovirus, either EBOV or MARV, resulted in formation of wild-type virus-like particles (VLPs) in mammalian cells. When used as a vaccine, the wild-type VLPs protected from homologous filovirus challenge. The aim of this work was to generate a multi-agent vaccine that would simultaneously protect against multiple and diverse members of the Filoviridae family. Our initial approach was to construct hybrid VLPs containing heterologous viral proteins, of EBOV and MARV, and test the efficacy of the hybrid VLPs in a guinea pig model. Our data indicate that vaccination with GP was required and sufficient to protect against a homologous filovirus challenge, as heterologous wild-type VLPs or hybrid VLPs that did not contain the homologous GP failed to protect. Alternately, we vaccinated guinea pigs with a mixture of wild-type Ebola and Marburg VLPs. Vaccination with a single dose of the multivalent VLP vaccine elicited strong immune responses to both viruses and protected animals against EBOV and MARV challenge. This work provides a critical foundation towards the development of a pan-filovirus vaccine that is safe and effective for use in primates and humans.

Animals↗
PubMed2004

Identification and partial characterization of Taastrup virus: a newly identified member species of the Mononegavirales.

We present a 8904-nt sequence of the central part of the RNA genome of a novel virus with a filovirus-like, nonidentical morphology named Taastrup virus (TV) detected in the leafhopper Psammotettix alienus. Sequence analysis identified five potential open reading frames (ORFs) and a complex pattern of homologies to various members of the Mononegavirales suggests a genome organization with the following order of genes: 3'-N-P-M-G-L-5'. Sequence analyses reveal an unusually large glycoprotein (G) containing both potential O-linked (14) and N-linked (9) glycosylation sites-a feature shared with the glycoproteins of Filoviridae and Pneumovirinae, and a nucleoprotein (N) with homology to the nucleoprotein of viral hemorrhagic septicemia virus (VHSV), a member of the Rhabdoviridae. Highly conserved domains were identified in the RNA-dependent RNA polymerase (L) between TV and other viruses within the order of Mononegavirales, and homology was found in particular with members of the Rhabdoviridae. The sequence similarities and the unique filovirus-like but nonidentical morphology unambiguously refer this newly identified virus to the order of Mononegavirales but to no family more than any, to other within the order.

Amino Acid Sequence↗
PubMed2003

A system of protein target sequences for anti-RNA-viral chemotherapy by a vitamin B6-derived zinc-chelating trioxa-adamantane-triol.

The synthesis of the structurally unusual heterotricyclic compound 1-[3-hydroxy-5-(hydroxymethyl)-2-methyl-4-pyridinyl]-2,8,9-trioxaadamantane-3,5,7-triol (trivially named bananin, BN) from pyridoxylidenephloroglucinol and a theoretical prospect on possible biological activities of BN are presented in this report. Pyridoxylidenephloroglucinol is synthesized by Knoevenagel condensation of the vitamin B6 aldehyde pyridoxal with phloroglucinol. Pyridoxylidenephloroglucinol rearranges to light-yellow (4'RS)-1',4'-dihydrobananin by refluxing in 5M hydrochloric acid. Air oxidation subsequently forms BN in the heat which immediately yields orange-yellow (4'RS)-4'-chloro-1',4'-dihydrobananin by 1,4-addition of hydrogen chloride. This intermediate could be isolated but, interestingly, not a BN hydrochloride. Brown BN is finally achieved by base-catalyzed elimination of hydrogen chloride from (4'RS)-4'-chloro-1',4'-dihydrobananin. Regarding possible biological activities, it was demonstrated that BN acts as zinc (Zn2+) chelator. Therefore, a target of interest could be the human immunodeficiency virus type 1 (HIV-1) zinc finger HIV-1 RNA-binding nucleocapsid protein p7 (NCp7). Through suggested zinc ejection from HIV-1 genomic RNA psi-element-binding and HIV-1-RNA-duplex packaging NCp7 by BN, thus rendering NCp7 functionally obsolete, it is deduced that HIV-1 replication and effective infectious virion encapsidation could be inhibited by BN. Furthermore, theoretical and structural considerations propose that BN is converted into bananin 5'-monophosphate (BNP) by the cell type-ubiquitous human enzyme pyridoxal kinase (EC 2.7.1.35). Together with the putative antilentiviral retinoid vitamin A-vitamin B6 conjugate analogue B6RA (Kesel, A. J. Biochem. Biophys. Res. Comm. 2003, 300, 793), BNP is postulated to serve as effector in a system of protein target sequences RX(D/E) of RNA virus components. Human immunodeficiency Retroviridae (HIVs) could possibly be influenced by B6RA and BNP. In addition, candidate targets of B6RA and BNP could be adsorption, transcription and/or viral RNA replication of an interestingly wide RNA virus selection including Picornaviridae (poliovirus, human coxsackievirus, hepatitis A virus), Flaviviridae (yellow fever virus, Dengue virus, West Nile virus, Kunjin virus, St. Louis encephalitis virus, hepatitis C virus), Togaviridae (rubella virus), Coronaviridae (human coronavirus, human SARS-associated coronavirus), Rhabdoviridae (rabies virus), Paramyxoviridae (human parainfluenza virus, measles virus, human respiratory syncytial virus), Filoviridae (Marburg virus, Ebola virus), Bornaviridae (Borna disease virus), Bunyaviridae (Hantaan virus), Arenaviridae (Lassa virus), and Reoviridae (human rotavirus). The postulated scope of 'metabolically trapped' BNP might resemble the antiviral spectrum of the RNA-viral virustatic ribavirin.

Adamantane↗
PubMed2003

Serological reactivity of baculovirus-expressed Ebola virus VP35 and nucleoproteins.

Ebola virus (EBOV) is a member of the family Filoviridae and is classified as a biosafety level 4 virus. This classification makes the preparation of antigen and performance of diagnostic assays time-consuming and complicated. The objective of this study was to evaluate the value of EBOV immunoassays based on recombinant nucleoprotein (r-NP) and recombinant VP35 (r-VP35) using large serum panels of African origin and from primates. Furthermore, we investigated whether the results obtained with EBOV r-VP35 enzyme-linked immunosorbent assay (ELISA) could improve on the findings obtained with the EBOV r-NP ELISA. The full-length EBOV NP and VP35 of the EBOV subtype Zaire were expressed as histidine-tagged recombinant proteins in the baculovirus expression system. The antigenic reactivity and specificity of these recombinant proteins were determined by Western blotting and ELISA using EBOV specific monoclonal antibodies. The results obtained with the r-NP and r-VP35 ELISAs were compared with the results obtained in an indirect immunofluorescence assay based on native EBOV subtype Zaire. EBOV specific monoclonal antibodies reacted specifically with the respective proteins in both Western blot and ELISA. Five hundred and twenty six samples from humans and primates were tested with r-NP and r-VP35 ELISAs. Monkey serum samples positive for EBOV subtype Reston and Zaire were both positive in the EBOV r-NP ELISA, whereas only the EBOV Zaire infected monkeys were positive in the r-VP35 ELISA. The sensitivity and specificity values of the EBOV recombinants' ELISAs compared to those of the immunofluorescence assay were 92% and 99% for r-NP and 44% and 100% for r-VP35. r-NP ELISA proved to be a sensitive and specific assay for EBOV diagnosis and for epidemiological studies for both EBOV subtypes Reston and Zaire. The use of r-VP35 in an ELISA format has no additional value for EBOV serodiagnosis.

Adolescent↗
PubMed1996

Initiation of Sendai virus multiplication from transfected cDNA or RNA with negative or positive sense.

BACKGROUND: The mononegavirus superfamily (Mononegavirales) comprises three families, Rhabdoviridae, Paramyxoviridae and Filoviridae. These viruses possess a single stranded negative sense RNA as the genome. Recent success in the recovery of infectious virus from a transfected cDNA of mononegaviruses including Sendai virus, a prototypic paramyxovirus, is opening the possibility of their genetic engineering. However, infectious viruses have been recovered only by initiating the infectious cycle with cDNA directing the synthesis of antigenomic positive sense (+)RNA. Starting with genomic negative sense (-)RNA has been unsuccessful. Furthermore, the recovery efficiency has often been extremely low. RESULTS: We describe here an analogous system that allows recovery of Sendai virus at a high rate, from cells in which the transfected cDNA and plasmids to support the synthesis of viral nucleocapsid protein and RNA polymerases are coexpressed by vaccinia virus-driven bacteriophage T7 polymerase. Our system was able to recover the virus from cDNA directing not only (+)RNA but also (-)RNA. Moreover, using this system, we succeeded in recovery of the virus by transfection of in vitro synthesized (+)RNA or (-)RNA. This improved virus recovery appeared to be accomplished by supplying the supporting plasmids at an optimal ratio and by minimizing the cytopathic effect of the vaccinia virus by specific inhibitors. In addition, it was probably critical that our cDNAs were constructed to generate viral authentic RNAs without adding T7 promoter-specific nucleotides to the 5' ends. An immediate application of the system was demonstrated by the creation of a candidate vaccine strain with a predetermined attenuating mutation in the cleavage-activation site of the viral fusion glycoprotein. CONCLUSION: We have established methods which greatly improve the recovery of Sendai virus from cDNA. There is essentially no absolute obstacle to recovery of the virus from the (-)RNA template. Even the complete full length RNA chain in the naked form appears to be properly encapsidated to become a functional template.

Amino Acid Sequence↗
PubMed1994

Genomic organization of Borna disease virus.

Borna disease virus is a neurotropic negative-strand RNA virus that infects a wide range of vertebrate hosts, causing disturbances in movement and behavior. We have cloned and sequenced the 8910-nucleotide viral genome by using RNA from Borna disease virus particles. The viral genome has complementary 3' and 5' termini and contains antisense information for five open reading frames. Homology to Filoviridae, Paramyxoviridae, and Rhabdoviridae is found in both cistronic and extracistronic regions. Northern analysis indicates that the virus transcribes mono- and polycistronic RNAs and uses termination/polyadenylylation signals reminiscent of those observed in other negative-strand RNA viruses. Borna disease virus is likely to represent a previously unrecognized genus, bornaviruses, or family, Bornaviridae, within the order Mononegavirales.

Amino Acid Sequence↗
PubMed1998

The central structural feature of the membrane fusion protein subunit from the Ebola virus glycoprotein is a long triple-stranded coiled coil.

The ectodomain of the Ebola virus Gp2 glycoprotein was solubilized with a trimeric, isoleucine zipper derived from GCN4 (pIIGCN4) in place of the hydrophobic fusion peptide at the N terminus. This chimeric molecule forms a trimeric, highly alpha-helical, and very thermostable molecule, as determined by chemical crosslinking and circular dichroism. Electron microscopy indicates that Gp2 folds into a rod-like structure like influenza HA2 and HIV-1 gp41, providing further evidence that viral fusion proteins from diverse families such as Orthomyxoviridae (Influenza), Retroviridae (HIV-1), and Filoviridae (Ebola) share common structural features, and suggesting a common membrane fusion mechanism.

Amino Acid Sequence↗
PubMedDate not supplied

Structural basis for membrane fusion by enveloped viruses.

Enveloped viruses such as HIV-1, influenza virus, and Ebola virus express a surface glycoprotein that mediates both cell attachment and fusion of viral and cellular membranes. The membrane fusion process leads to the release of viral proteins and the RNA genome into the host cell, initiating an infectious cycle. This review focuses on the HIV-1 gp41 membrane fusion protein and discusses the structural similarities of viral membrane fusion proteins from diverse families such as Retroviridae (HIV-1), Orthomyxoviridae (influenza virus), and Filoviridae (Ebola virus). Their structural organization suggests that they have all evolved to use a similar strategy to promote fusion of viral and cellular membranes. This observation led to the proposal of a general model for viral membrane fusion, which will be discussed in detail.

Animals↗
PubMed2004

Marburg and Ebola viruses as aerosol threats.

Ebola and Marburg viruses are the sole members of the genus Filovirus in the family Filoviridae. There has been considerable media attention and fear generated by outbreaks of filoviruses because they can cause a severe viral hemorrhagic fever (VHF) syndrome that has a rapid onset and high mortality. Although they are not naturally transmitted by aerosol, they are highly infectious as respirable particles under laboratory conditions. For these and other reasons, filoviruses are classified as category A biological weapons. However, there is very little data from animal studies with aerosolized filoviruses. Animal models of filovirus exposure are not well characterized, and there are discrepancies between these models and what has been observed in human outbreaks. Building on published results from aerosol studies, as well as a review of the history, epidemiology, and disease course of naturally occurring outbreaks, we offer an aerobiologist's perspective on the threat posed by aerosolized filoviruses.

Aerosols↗