The Experts below are selected from a list of 270 Experts worldwide ranked by ideXlab platform
Monique Lafon - One of the best experts on this subject based on the ideXlab platform.
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Rabies Virus receptors
Journal of NeuroVirology, 2005Co-Authors: Monique LafonAbstract:There is convincing in vitro evidence that the muscular form of the nicotinic acetylcholine receptor (nAChR), the neuronal cell adhesion molecule (NCAM), and the p75 neurotrophin receptor (p75NTR) bind Rabies Virus and/or facilitate Rabies Virus entry into cells. Other components of the cell membrane, such as gangliosides, may also participate in the entry of Rabies Virus. However, little is known of the role of these molecules in vivo. This review proposes a speculative model that accounts for the role of these different molecules in entry and trafficking of Rabies Virus into the nervous system.
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the neural cell adhesion molecule is a receptor for Rabies Virus
Journal of Virology, 1998Co-Authors: Maria-isabel Thoulouze, Mireille Lafage, Melitta Schachner, Ursula Hartmann, Harold Cremer, Monique LafonAbstract:Previous reports strongly suggest that, in addition to the nicotinic acetylcholine receptor, Rabies Virus can use other, as-yet-unidentified receptors. We found that laboratory cell lines susceptible to Rabies Virus infection express the neural cell adhesion molecule (NCAM) (CD56) on their surface, whereas resistant cells do not, supporting the idea that NCAM could be a Rabies Virus receptor. We observed that (i) incubation with Rabies Virus decreases the surface expression of NCAM; (ii) treatment of susceptible cells with heparan sulfate, a ligand for NCAM, or with NCAM antibodies significantly reduces the Rabies Virus infection; and (iii) preincubation of Rabies Virus inoculum with soluble NCAM protein as a receptor decoy drastically neutralizes the capacity of Rabies Virus to infect susceptible cells. Moreover, we demonstrated that transfection of resistant L fibroblasts with the NCAM-encoding gene induces Rabies Virus susceptibility whereas absence of NCAM in the primary cortical cell cultures prepared from NCAM-deficient mice reduces the Rabies Virus infection and Virus production. This provides evidence that NCAM is an in vitro receptor for the Rabies Virus. Moreover, the in vivo relevance for the use of NCAM as a receptor was demonstrated by the infection of NCAM-deficient mice, in which Rabies mortality was delayed and brain invasion by Rabies Virus was drastically restricted. Our results showed that NCAM, which is expressed mainly in the adult nervous system, plays an important role in Rabies infection. However, it cannot be excluded that receptors other than NCAM are utilized. Thus, the description of NCAM as a new Rabies Virus receptor would be another example of the use by Viruses of more than one receptor to gain entry into the host.
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Rabies Virus infects mouse and human lymphocytes and induces apoptosis.
Journal of Virology, 1997Co-Authors: Maria-isabel Thoulouze, Mireille Lafage, Juan Antonio Montaño-hirose, Monique LafonAbstract:Attenuated and highly neurovirulent Rabies Virus strains have distinct cellular tropisms. Highly neurovirulent strains such as the challenge Virus standard (CVS) are highly neurotropic, whereas the attenuated strain ERA also infects nonneuronal cells. We report that both Rabies Virus strains infect activated murine lymphocytes and the human lymphoblastoid Jurkat T-cell line in vitro. The lymphocytes are more permissive to the attenuated ERA Rabies Virus strain than to the CVS strain in both cases. We also report that in contrast to that of the CVS strain, ERA viral replication induces apoptosis of infected Jurkat T cells, and cell death is concomitant with viral glycoprotein expression, suggesting that this protein has a role in the induction of apoptosis. Our data indicate that (i) Rabies Virus infects lymphocytes, (ii) lymphocyte infection with the attenuated Rabies Virus strain causes apoptosis, and (iii) apoptosis does not hinder Rabies Virus production. In contrast to CVS, ERA Rabies Virus and other attenuated Rabies Virus vaccines stimulate a strong immune response and are efficient live vaccines. The paradoxical finding that a Rabies Virus triggers a strong immune response despite the fact that it infects lymphocytes and induces apoptosis is discussed in terms of the function of apoptosis in the immune response.
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Human monoclonal antibodies specific for the Rabies Virus glycoprotein and N protein
Journal of General Virology, 1990Co-Authors: Monique Lafon, Lena Edelman, Jean Pierre Bouvet, Mireille Lafage, Elizabeth MontchâtreAbstract:Human monoclonal antibodies to Rabies Virus were established by Epstein-Barr Virus infection of peripheral blood lymphocytes collected from a Rabies-vaccinated donor, and fusion with a heteromyeloma line. Two human monoclonal antibodies, HUM1 and HUM2, both IgG2, reacted with the envelope glycoprotein of the Rabies Virus. The antibody HUM1 neutralized Rabies Virus (lyssaVirus serotype 1) and Mokola Virus (lyssaVirus serotype 3), but did not neutralize European bat lyssaVirus, suggesting that some common antigenicity exists between the glycoproteins of serotypes 1 and 3. In addition, this antibody neutralized a series of Viruses resistant to neutralization by antibodies recognizing, in a murine system, antigenic sites I, II and III; however, it failed to neutralize Viruses altered at site VI, indicating that human monoclonal antibody HUM1 is directed against antigenic site VI. The other human anti-glycoprotein antibody, HUM2, neutralized the European bat lyssaVirus in addition to serotypes 1 and 3, but none of the resistant variant Viruses altered at the sites mentioned above. A third human monoclonal antibody, HUM3 (IgM), was reactive with the internal nucleoprotein of the Rabies Virus. This antibody contained a murine light chain corresponding to the cytoplasmic murine chain not secreted in the heteromyeloma line. The potential use of monoclonal antibodies in post-exposure treatment of Rabies is discussed.
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Characterization of Human Monoclonal Antibodies Specific for the Rabies Virus
From Clone to Clinic, 1990Co-Authors: Lena Edelman, Monique LafonAbstract:Human monoclonal antibodies to Rabies Virus were established by EBV infection of peripheral blood lymphocytes collected from a Rabies- vaccinated donor, and fusion with heteromyeloma line. Two human monoclonal antibodies, HUM1 and HUM2, both IgG2, reacted with the envelope glycoprotein of the Rabies Virus. A third human monoclonal antibody, HUM3 (IgM), was reactive with the internal nucleoprotein (N protein) of the Rabies Virus. This non-neutralizing antibody contained a murine light chain corresponding to the cytoplasmic murine chain non secreted in the heteromyeloma line.
Charles E. Rupprecht - One of the best experts on this subject based on the ideXlab platform.
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evidence of Rabies Virus exposure among humans in the peruvian amazon
American Journal of Tropical Medicine and Hygiene, 2012Co-Authors: Amy T Gilbert, Michael Niezgoda, Brett W Petersen, Sergio Recuenco, Jorge Gomez, Alberto V Lagunatorres, Charles E. RupprechtAbstract:In May of 2010, two communities (Truenococha and Santa Marta) reported to be at risk of vampire bat depredation were surveyed in the Province Datem del Maranon in the Loreto Department of Peru. Risk factors for bat exposure included age less than or equal to 25 years and owning animals that had been bitten by bats. Rabies Virus neutralizing antibodies (rVNAs) were detected in 11% (7 of 63) of human sera tested. Rabies Virus ribonucleoprotein (RNP) immunoglobulin G (IgG) antibodies were detected in the sera of three individuals, two of whom were also seropositive for rVNA. Rabies Virus RNP IgM antibodies were detected in one respondent with no evidence of rVNA or RNP IgG antibodies. Because one respondent with positive rVNA results reported prior vaccination and 86% (six of seven) of rVNA-positive respondents reported being bitten by bats, these data suggest nonfatal exposure of persons to Rabies Virus, which is likely associated with vampire bat depredation.
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Rabies surveillance in the United States evaluation of Rabies Virus variants
2012Co-Authors: Jessie L. Dyer, Jesse D. Blanton, Charles E. RupprechtAbstract:During 2011, 49 states and Puerto Rico reported 6,031 rabid animals representing a 1.9% decrease from the 6,153 rabid animals reported in 2010. Relative contributions by the major animal groups were as follows: 1,981 raccoons (32.8%), 1,627 skunks (27.0%), 1,380 bats (22.9%), 427 foxes (7.1%), 303 cats (5.0%), 65 cattle (1.1%), and 70 dogs (1.2%). Compared to 2010, a significant increase was reported among rabid skunks. Canine Rabies Virus transmission has been eliminated in the United States since 2004 and monitoring the Rabies Virus variant associated with rabid domestic animals is critical. We evaluated Rabies diagnostic submission data for the US from 2008-2011 for reported rabid dogs, cats and coyotes. A total of 1,546 rabid cats, dogs and coyotes were reported, with Rabies Virus variants characterized in 35%. Cats comprised the majority of rabid animals not characterized. No canine Rabies Virus variants were reported. Most rabid domestic animals were infected with the Rabies Virus variant circulating in the predominant mesocarnivore reservoir from the geographic area of submission. However, isolated cases associated with bat Rabies Virus variants were reported. These findings highlight the need for enhanced surveillance to monitor the circulation of Rabies Virus variants in local carnivore populations to determine emergence of new Rabies Virus variants. State health departments may not test suspect rabid animals unless a human exposure occurs. Moreover, variant typing is not performed on all samples though CDC provides Rabies Virus characterization, if requested. The public health implications of host shifts and potential spillover of Rabies Virus variants from wildlife to domestic animals reinforces the need for additional laboratory diagnostics.
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first myotis lucifugus Rabies Virus variant detected in a human
Revista de Educação Continuada em Medicina Veterinária e Zootecnia do CRMV-SP, 2012Co-Authors: Lillian A Orciari, Richard Franka, Catherine M Brown, V Lijewski, Felix R Jackson, Michael Niezgoda, D Track, Pamela A Yager, Dillon Hightower, Charles E. RupprechtAbstract:A 63 year old male from Barnstable County, MA was evaluated at Massachusetts tertiary care facility for possible stroke and encephalitis. Although the patient’s first symptoms were joint stiffness, within 2 days the patient was exhibiting signs of hydrophobia, and acute progressive encephalitis. Serum, CSF, nuchal (skin) biopsy, and saliva samples from the patient were sent to CDC for Rabies diagnostic testing. No Rabies Virus IgG or IgM antibodies were detected in serum and CSF by the indirect fluorescent antibody (IFA) test, and no viral neutralizing antibodies were detected in the serum or CSF samples by the rapid fluorescent focus inhibition test (RFFIT). Rabies Virus antigen was detected in nuchal biopsy samples using direct fluorescent antibody (DFA) test. Nested (and heminested) RT-PCR amplicons were produced from skin and saliva using multiple Rabies Virus nucleoprotein gene primers sets. Sequence analysis of the entire nucleoprotein gene and comparisons with samples in the CDC database and Genbank indicated that the Rabies Virus variant was associated with Myotis sp bats. Further analysis of phylogenetic trees (1000) by Neighbor Joining, Maximum Parsimony and Maximum Likelihood indicated the variant was most parsimonious with the common “little brown bat” Myotis lucifugus. Postmortem brain tissues were positive for Rabies Virus antigen by the direct fluorescent antibody test. Antigenic typing with monoclonal antibodies to the Rabies Virus nucleoprotein was consistent with the previous results of a bat Rabies variant, but lacked the resolution of genetic typing methods. Sequence analysis of the RT-PCR amplicons from the complete nucleoprotein gene were consistent with the previous findings of the variant seen in M. lucifugus. Although M. lucifugus is common in the US and frequently has had known encounters with humans and animals, this is the first documented case of this Rabies Virus variant in a human. In contrast to this unique finding, the Rabies Virus variant associated with a solitary bat with rare known human or animal encounters Lasionycteris noctivagans (silver-haired bat) has been responsible for most human Rabies cases in the USA over the last 2 decades.
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Live attenuated Rabies Virus co-infected with street Rabies Virus protects animals against Rabies.
Vaccine, 2011Co-Authors: Xianfu Wu, Richard Franka, Heather Henderson, Charles E. RupprechtAbstract:While current Rabies post-exposure prophylaxis (PEP) is highly effective, it is costly and the vaccination regimen is complicated, requiring both inactivated vaccines and immunoglobulins. A one-dose Rabies vaccine for human PEP remains a long-term goal. Here, we describe development of a highly attenuated Rabies Virus ERAg3m, with a mutation in the glycoprotein (G) gene and a switch of the G gene with the matrix protein gene in the viral genome. After a one-dose intramuscular vaccination, the ERAg3m Virus protected 100% of mice and hamsters from lethal challenge. In co-infections, using a lethal dose of street Rabies Virus mixed with ERAg3m, 100% of hamsters and 90% of mice survived and were protected against subsequent infection. A mock co-infection, using inactivated commercial human Rabies vaccine and a lethal dose of street Rabies Virus, protected 100% and 40% of hamsters and mice, respectively. In co-infections, when vaccine was administrated in the left leg and challenge Virus in the right leg, the ERAg3m Virus protected 40% of mice, while the inactivated vaccine showed no protection. Therefore, live attenuated Rabies Virus when given pre-exposure or co-infected with street Rabies Virus, is capable of preventing Rabies in two different animal models. Overall, this highly attenuated live Rabies Virus offered better protection than the inactivated vaccine.
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Glycoprotein gene relocation in Rabies Virus
Virus Research, 2007Co-Authors: Xianfu Wu, Charles E. RupprechtAbstract:Abstract Unlike vesicular stomatitis Virus, Rabies Virus glycoprotein gene has not been successfully relocated closer to promoter–proximal regions by reverse genetics. Here we describe an efficient system for the Evelyn-Rokitnicki-Abelseth (ERA) Rabies Virus with the glycoprotein gene switched with the matrix protein gene, creating a reshuffled Virus ERAgm (gene order N-P-G-M-L). With the aid of an autogene plasmid, the T7 RNA polymerase containing a nuclear location signal from the SV40 large T antigen facilitated Virus recovery. The rearranged ERAgm Rabies Virus replicated as well as the parental ERA (gene order N-P-M-G-L) Virus, reaching 10 9 ffu/ml in infected BSR cells. The altered glycoprotein gene position in viral genome presented an alternative way to study the pathogenicity of Rabies Virus. This also provides a potential novel method for Rabies vaccine development.
Michael Niezgoda - One of the best experts on this subject based on the ideXlab platform.
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evidence of Rabies Virus exposure among humans in the peruvian amazon
American Journal of Tropical Medicine and Hygiene, 2012Co-Authors: Amy T Gilbert, Michael Niezgoda, Brett W Petersen, Sergio Recuenco, Jorge Gomez, Alberto V Lagunatorres, Charles E. RupprechtAbstract:In May of 2010, two communities (Truenococha and Santa Marta) reported to be at risk of vampire bat depredation were surveyed in the Province Datem del Maranon in the Loreto Department of Peru. Risk factors for bat exposure included age less than or equal to 25 years and owning animals that had been bitten by bats. Rabies Virus neutralizing antibodies (rVNAs) were detected in 11% (7 of 63) of human sera tested. Rabies Virus ribonucleoprotein (RNP) immunoglobulin G (IgG) antibodies were detected in the sera of three individuals, two of whom were also seropositive for rVNA. Rabies Virus RNP IgM antibodies were detected in one respondent with no evidence of rVNA or RNP IgG antibodies. Because one respondent with positive rVNA results reported prior vaccination and 86% (six of seven) of rVNA-positive respondents reported being bitten by bats, these data suggest nonfatal exposure of persons to Rabies Virus, which is likely associated with vampire bat depredation.
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first myotis lucifugus Rabies Virus variant detected in a human
Revista de Educação Continuada em Medicina Veterinária e Zootecnia do CRMV-SP, 2012Co-Authors: Lillian A Orciari, Richard Franka, Catherine M Brown, V Lijewski, Felix R Jackson, Michael Niezgoda, D Track, Pamela A Yager, Dillon Hightower, Charles E. RupprechtAbstract:A 63 year old male from Barnstable County, MA was evaluated at Massachusetts tertiary care facility for possible stroke and encephalitis. Although the patient’s first symptoms were joint stiffness, within 2 days the patient was exhibiting signs of hydrophobia, and acute progressive encephalitis. Serum, CSF, nuchal (skin) biopsy, and saliva samples from the patient were sent to CDC for Rabies diagnostic testing. No Rabies Virus IgG or IgM antibodies were detected in serum and CSF by the indirect fluorescent antibody (IFA) test, and no viral neutralizing antibodies were detected in the serum or CSF samples by the rapid fluorescent focus inhibition test (RFFIT). Rabies Virus antigen was detected in nuchal biopsy samples using direct fluorescent antibody (DFA) test. Nested (and heminested) RT-PCR amplicons were produced from skin and saliva using multiple Rabies Virus nucleoprotein gene primers sets. Sequence analysis of the entire nucleoprotein gene and comparisons with samples in the CDC database and Genbank indicated that the Rabies Virus variant was associated with Myotis sp bats. Further analysis of phylogenetic trees (1000) by Neighbor Joining, Maximum Parsimony and Maximum Likelihood indicated the variant was most parsimonious with the common “little brown bat” Myotis lucifugus. Postmortem brain tissues were positive for Rabies Virus antigen by the direct fluorescent antibody test. Antigenic typing with monoclonal antibodies to the Rabies Virus nucleoprotein was consistent with the previous results of a bat Rabies variant, but lacked the resolution of genetic typing methods. Sequence analysis of the RT-PCR amplicons from the complete nucleoprotein gene were consistent with the previous findings of the variant seen in M. lucifugus. Although M. lucifugus is common in the US and frequently has had known encounters with humans and animals, this is the first documented case of this Rabies Virus variant in a human. In contrast to this unique finding, the Rabies Virus variant associated with a solitary bat with rare known human or animal encounters Lasionycteris noctivagans (silver-haired bat) has been responsible for most human Rabies cases in the USA over the last 2 decades.
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identification and characterization of a human monoclonal antibody that potently neutralizes a broad panel of Rabies Virus isolates
Vaccine, 2007Co-Authors: Susan E Sloan, Jesse D. Blanton, Michael Niezgoda, Cathleen A Hanlon, William C Weldon, Josh Self, Kirk J Rowley, Robert Mandell, Gregory J Babcock, William D ThomasAbstract:Rabies is a zoonosis that results in millions of human exposures worldwide each year. Human monoclonal antibodies (HuMAbs) that neutralize Rabies Virus may represent one viable strategy for post-exposure prophylaxis in humans, and have many advantages over current human or equine Rabies immune globulin. Transgenic mice carrying human immunoglobulin genes were used to isolate human monoclonal antibodies that neutralized Rabies Virus. Several HuMAbs were identified that neutralized Rabies Virus variants from a broad panel of isolates of public health significance. HuMAb 17C7 was the most promising antibody identified because it neutralized all Rabies Virus isolates tested. HuMAb 17C7 recognizes a conformational epitope on the Rabies Virus glycoprotein which includes antigenic site III. HuMAb 17C7 protected hamsters from a lethal dose of Rabies Virus in a well-established in vivo model of post-exposure prophylaxis.
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novel Rabies Virus neutralizing epitope recognized by human monoclonal antibody fine mapping and escape mutant analysis
Journal of Virology, 2005Co-Authors: Wilfred E Marissen, Michael Niezgoda, William C Weldon, Arjen R Kramer, Amy B Rice, Milosz Faber, Jerry W Slootstra, Rob H Meloen, Marieke Clijstersvan Der Horst, Therese VisserAbstract:Anti-Rabies Virus immunoglobulin combined with Rabies vaccine protects humans from lethal Rabies infections. For cost and safety reasons, replacement of the human or equine polyclonal immunoglobulin is advocated, and the use of Rabies Virus-specific monoclonal antibodies (MAbs) is recommended. We produced two previously described potent Rabies Virus-neutralizing human MAbs, CR57 and CRJB, in human PER.C6 cells. The two MAbs competed for binding to Rabies Virus glycoprotein. Using CR57 and a set of 15-mer overlapping peptides covering the glycoprotein ectodomain, a neutralization domain was identified between amino acids (aa) 218 and 240. The minimal binding region was identified as KLCGVL (aa 226 to 231), with key residues K-CGV- identified by alanine replacement scanning. The critical binding region of this novel nonconformational Rabies Virus epitope is highly conserved within Rabies Viruses of genotype 1. Subsequently, we generated six Rabies Virus variants escaping neutralization by CR57 and six variants escaping CRJB. The CR57 escape mutants were only partially covered by CRJB, and all CRJB-resistant variants completely escaped neutralization by CR57. Without exception, the CR57-resistant variants showed a mutation at key residues within the defined minimal binding region, while the CRJB escape Viruses showed a single mutation distant from the CR57 epitope (N182D) combined with mutations in the CR57 epitope. The competition between CR57 and CRJB, the in vitro escape profile, and the apparent overlap between the recognized epitopes argues against including both CR57 and CRJB in a MAb cocktail aimed at replacing classical immunoglobulin preparations.
Bernhard Dietzschold - One of the best experts on this subject based on the ideXlab platform.
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the development of monoclonal human Rabies Virus neutralizing antibodies as a substitute for pooled human immune globulin in the prophylactic treatment of Rabies Virus exposure
Journal of Immunological Methods, 2000Co-Authors: J M Champion, Charles E. Rupprecht, Bernhard Dietzschold, Abner Louis Notkins, Hilary Koprowski, Rhonda B Kean, D C HooperAbstract:Abstract To provide a more defined and safer replacement for the human Rabies immune globulin (HRIG) from pooled serum which is currently used for treatment of exposure to Rabies Virus we have developed a series of human Rabies Virus-specific monoclonal antibodies. Mouse–human heterohybrid myeloma cells producing Rabies Virus-specific human monoclonal antibodies were prepared using B cells obtained from volunteers recently-immunized with a commercial Rabies Virus vaccine (HDCV). Cell lines producing antibody which neutralized the Evelyn–Rokitnicki–Abelseth (ERA) Rabies Virus strain in vitro were cloned and the resulting monoclonal antibodies characterized for isotype, specificity against a variety of Rabies Virus isolates, and neutralization capacity. The ability of the monoclonal antibodies to neutralize a variety of Rabies Virus strains in vitro correlated with their binding specificity for these Viruses in an enzyme-linked immunoadsorbant assay (ELISA). A number of these antibodies have proven suitable for the formulation of a prophylactic human monoclonal antibody-based reagent which would provide significant advantages to the HRIG in having defined, reproducible specificity, lessened possibility of contamination with viral pathogens, and consistent availability.
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pathogenicity of different Rabies Virus variants inversely correlates with apoptosis and Rabies Virus glycoprotein expression in infected primary neuron cultures
Journal of Virology, 1999Co-Authors: Kinjiro Morimoto, Hilary Koprowski, Craig D Hooper, Sergei Spitsin, Bernhard DietzscholdAbstract:The mouse-adapted Rabies Virus strain CVS-24 has stable variants, CVS-B2c and CVS-N2c, which differ greatly in their pathogenicity for normal adult mice and in their ability to infect nonneuronal cells. The glycoprotein (G protein), which has previously been implicated in Rabies Virus pathogenicity, shows substantial structural differences between these variants. Although prior studies have identified antigenic site III of the G protein as the major pathogenicity determinant, CVS-B2c and CVS-N2c do not vary at this site. The possibility that pathogenicity is inversely related to G protein expression levels is suggested by the finding that CVS-B2c, the less pathogenic variant, expresses at least fourfold-higher levels of G protein than CVS-N2c in infected neurons. Although there is some difference between CVS-B2c- and CVS-N2c-infected neurons in G protein mRNA expression levels, the differential expression of G protein appears to be largely determined by posttranslational mechanisms that affect G protein stability. Pulse-chase experiments indicated that the G protein of CVS-B2c is degraded more slowly than that of CVS-N2c. The accumulation of G protein correlated with the induction of programmed cell death in CVS-B2c-infected neurons. The extent of apoptosis was considerably lower in CVS-N2c-infected neurons, where G protein expression was minimal. While nucleoprotein (N protein) expression levels were similar in neurons infected with either variant, the transport of N protein into neuronal processes was strongly inhibited in CVS-B2c-infected cells. Thus, downregulation of G protein expression in neuronal cells evidently contributes to Rabies Virus pathogenesis by preventing apoptosis and the apparently associated failure of the axonal transport of N protein.
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Inhibition of Rabies Virus Infection by an Oligodeoxynucleotide Complementary to Rabies Virus Genomic RNA
Antisense & Nucleic Acid Drug Development, 1996Co-Authors: Zhen Fang Fu, Bernhard Dietzschold, Eric Wickstrom, Ming Jiang, S. Corisdeo, Jun Yang, Hilary KoprowskiAbstract:To develop antiRabies Virus-specific agents, eight oligodeoxynucleotides (ODN) complementary to either Rabies Virus genomic RNA (negative polarity) or Rabies Virus transcripts (mRNA) were synthesized and tested for their activity to inhibit Rabies Virus infection in cell cultures. It was found that the ODN RH+1 complementary to Rabies Virus genomic RNA blocked almost completely Rabies Virus infection at concentrations as low as 2 μM, whereas ODN complementary to viral transcripts did poorly even at concentrations as high as 20 μM. The antigenomic ODN also has the ability to inhibit cell-to-cell spread of Rabies Virus, which is an indicator for protection of Rabies Virus infection in vivo. These results indicate that ODN complementary to Rabies Virus genomic RNA have strong ability to inhibit Rabies Virus infection in cell culture and may have the potential to be used for therapy in clinical Rabies.
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Inhibition of immune responses against Rabies Virus by monoclonal antibodies directed against Rabies Virus antigens.
Vaccine, 1992Co-Authors: Carolin L. Schumacher, Hildegund C J Ertl, Hilary Koprowski, Bernhard DietzscholdAbstract:Abstract Treatment of mice with a cocktail of murine anti-Rabies monoclonal antibodies (mAb-C) interfered with the ability of these animals to mount a Virus-neutralizing antibody response to Rabies vaccine. Administered mAb-C did not affect the induction of Rabies Virus-specific T-helper cells. The magnitude of the inhibition of Rabies Virus-specific B-cell response was dependent on the concentration of the mAb-C and the duration of the mAb-mediated interference was inversely proportional to the biological half-life of the mAb. As long as the serum titres were above a critical threshold, the suppression could not be overcome even by multiple vaccinations. Since injection of mice with immunocomplexes consisting of inactivated Rabies Virus and mAb rendered the animals non-responsive to a subsequent vaccination with inactivated Rabies Virus, it is concluded that the mAb-induced suppression might be caused by the formation of antigen-antibody complexes which exert a negative signalling effect to premature B cells.
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Biological characterization of human monoclonal antibodies to Rabies Virus.
Journal of Virology, 1990Co-Authors: Bernhard Dietzschold, Charles E. Rupprecht, M. Gore, Paolo Casali, Yoshihiko Ueki, Abner Louis Notkins, Hilary KoprowskiAbstract:Rabies Virus antigen-specific human monoclonal antibodies (MAbs) that recognized either viral glycoprotein, ribonucleoprotein, or matrix proteins were generated. Only glycoprotein-specific MAb neutralized a variety of Rabies Viruses and protected laboratory rodents against lethal Rabies Virus infection. The determinant recognized by this MAb does not appear to reside in previously defined antigenic sites of the viral glycoprotein.
Hilary Koprowski - One of the best experts on this subject based on the ideXlab platform.
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the development of monoclonal human Rabies Virus neutralizing antibodies as a substitute for pooled human immune globulin in the prophylactic treatment of Rabies Virus exposure
Journal of Immunological Methods, 2000Co-Authors: J M Champion, Charles E. Rupprecht, Bernhard Dietzschold, Abner Louis Notkins, Hilary Koprowski, Rhonda B Kean, D C HooperAbstract:Abstract To provide a more defined and safer replacement for the human Rabies immune globulin (HRIG) from pooled serum which is currently used for treatment of exposure to Rabies Virus we have developed a series of human Rabies Virus-specific monoclonal antibodies. Mouse–human heterohybrid myeloma cells producing Rabies Virus-specific human monoclonal antibodies were prepared using B cells obtained from volunteers recently-immunized with a commercial Rabies Virus vaccine (HDCV). Cell lines producing antibody which neutralized the Evelyn–Rokitnicki–Abelseth (ERA) Rabies Virus strain in vitro were cloned and the resulting monoclonal antibodies characterized for isotype, specificity against a variety of Rabies Virus isolates, and neutralization capacity. The ability of the monoclonal antibodies to neutralize a variety of Rabies Virus strains in vitro correlated with their binding specificity for these Viruses in an enzyme-linked immunoadsorbant assay (ELISA). A number of these antibodies have proven suitable for the formulation of a prophylactic human monoclonal antibody-based reagent which would provide significant advantages to the HRIG in having defined, reproducible specificity, lessened possibility of contamination with viral pathogens, and consistent availability.
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pathogenicity of different Rabies Virus variants inversely correlates with apoptosis and Rabies Virus glycoprotein expression in infected primary neuron cultures
Journal of Virology, 1999Co-Authors: Kinjiro Morimoto, Hilary Koprowski, Craig D Hooper, Sergei Spitsin, Bernhard DietzscholdAbstract:The mouse-adapted Rabies Virus strain CVS-24 has stable variants, CVS-B2c and CVS-N2c, which differ greatly in their pathogenicity for normal adult mice and in their ability to infect nonneuronal cells. The glycoprotein (G protein), which has previously been implicated in Rabies Virus pathogenicity, shows substantial structural differences between these variants. Although prior studies have identified antigenic site III of the G protein as the major pathogenicity determinant, CVS-B2c and CVS-N2c do not vary at this site. The possibility that pathogenicity is inversely related to G protein expression levels is suggested by the finding that CVS-B2c, the less pathogenic variant, expresses at least fourfold-higher levels of G protein than CVS-N2c in infected neurons. Although there is some difference between CVS-B2c- and CVS-N2c-infected neurons in G protein mRNA expression levels, the differential expression of G protein appears to be largely determined by posttranslational mechanisms that affect G protein stability. Pulse-chase experiments indicated that the G protein of CVS-B2c is degraded more slowly than that of CVS-N2c. The accumulation of G protein correlated with the induction of programmed cell death in CVS-B2c-infected neurons. The extent of apoptosis was considerably lower in CVS-N2c-infected neurons, where G protein expression was minimal. While nucleoprotein (N protein) expression levels were similar in neurons infected with either variant, the transport of N protein into neuronal processes was strongly inhibited in CVS-B2c-infected cells. Thus, downregulation of G protein expression in neuronal cells evidently contributes to Rabies Virus pathogenesis by preventing apoptosis and the apparently associated failure of the axonal transport of N protein.
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Inhibition of Rabies Virus Infection by an Oligodeoxynucleotide Complementary to Rabies Virus Genomic RNA
Antisense & Nucleic Acid Drug Development, 1996Co-Authors: Zhen Fang Fu, Bernhard Dietzschold, Eric Wickstrom, Ming Jiang, S. Corisdeo, Jun Yang, Hilary KoprowskiAbstract:To develop antiRabies Virus-specific agents, eight oligodeoxynucleotides (ODN) complementary to either Rabies Virus genomic RNA (negative polarity) or Rabies Virus transcripts (mRNA) were synthesized and tested for their activity to inhibit Rabies Virus infection in cell cultures. It was found that the ODN RH+1 complementary to Rabies Virus genomic RNA blocked almost completely Rabies Virus infection at concentrations as low as 2 μM, whereas ODN complementary to viral transcripts did poorly even at concentrations as high as 20 μM. The antigenomic ODN also has the ability to inhibit cell-to-cell spread of Rabies Virus, which is an indicator for protection of Rabies Virus infection in vivo. These results indicate that ODN complementary to Rabies Virus genomic RNA have strong ability to inhibit Rabies Virus infection in cell culture and may have the potential to be used for therapy in clinical Rabies.
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Inhibition of immune responses against Rabies Virus by monoclonal antibodies directed against Rabies Virus antigens.
Vaccine, 1992Co-Authors: Carolin L. Schumacher, Hildegund C J Ertl, Hilary Koprowski, Bernhard DietzscholdAbstract:Abstract Treatment of mice with a cocktail of murine anti-Rabies monoclonal antibodies (mAb-C) interfered with the ability of these animals to mount a Virus-neutralizing antibody response to Rabies vaccine. Administered mAb-C did not affect the induction of Rabies Virus-specific T-helper cells. The magnitude of the inhibition of Rabies Virus-specific B-cell response was dependent on the concentration of the mAb-C and the duration of the mAb-mediated interference was inversely proportional to the biological half-life of the mAb. As long as the serum titres were above a critical threshold, the suppression could not be overcome even by multiple vaccinations. Since injection of mice with immunocomplexes consisting of inactivated Rabies Virus and mAb rendered the animals non-responsive to a subsequent vaccination with inactivated Rabies Virus, it is concluded that the mAb-induced suppression might be caused by the formation of antigen-antibody complexes which exert a negative signalling effect to premature B cells.
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Biological characterization of human monoclonal antibodies to Rabies Virus.
Journal of Virology, 1990Co-Authors: Bernhard Dietzschold, Charles E. Rupprecht, M. Gore, Paolo Casali, Yoshihiko Ueki, Abner Louis Notkins, Hilary KoprowskiAbstract:Rabies Virus antigen-specific human monoclonal antibodies (MAbs) that recognized either viral glycoprotein, ribonucleoprotein, or matrix proteins were generated. Only glycoprotein-specific MAb neutralized a variety of Rabies Viruses and protected laboratory rodents against lethal Rabies Virus infection. The determinant recognized by this MAb does not appear to reside in previously defined antigenic sites of the viral glycoprotein.
