58 Therapeutic Activity of an Anti-Idiotypic Antibody-Derived Killer Peptide against Influenza A Virus Experimental Infection. Giorgio Conti,1 Walter Magliani,1 Stefania Conti,1 Lucia Nencioni,2 Rossella Sgarbanti,2 Anna Teresa Palamara,2 and Luciano Polonelli1* Department of Pathology and Laboratory Medicine, Microbiology Section, University of Parma, Parma, Italy1, Department of Public Health Sciences, Pharmaceutical Microbiology Section, University of Rome La Sapienza, Rome, Italy2 The “in vitro” and “in vivo” activities of a killer decapeptide (KP) against influenza A virus is described, and the mechanisms of action are suggested. KP represents the functional internal image of a yeast killer toxin that proved to exert antimicrobial and anti-human immunodeficiency virus type 1 (HIV-1) activities. Treatment with KP demonstrated a significant inhibitory activity on the replication of two strains of influenza A virus in different cell lines, as evaluated by hemagglutination, hemadsorption, and plaque assays. The complete inhibition of virus particle production and a marked reduction of the synthesis of viral proteins (membrane protein and hemagglutinin, in particular) were observed at a KP concentration of 4 μg/ml. Moreover, KP administered intraperitoneally at a dose of 100 μg/mice once a day for 10 days to influenza A/NWS/33 (H1N1) virus-infected mice improved the survival of the animals by 40% and significantly decreased the viral titers in their lungs. Overall, KP appears to be the first anti-idiotypic antibody-derived peptide that displays inhibitory activity and that has a potential therapeutic effect against pathogenic microorganisms. Even if the precise molecular mechanism by which KP can interferewith viral multiplication remains to be determined, our results suggest that adsorption and fusion are not affected, as reported from studies with monoclonal Ab HC63. According to the experimental conditions adopted, in the presence of KP, appreciable reductions in the levels of viral proteins, including glycosylated forms, have been observed. In particular, M1 and HA synthesis in the late phase of viral multiplication were mainly affected. These findings support the hypothesis that the marked reduction of M1 synthesis may be the major cause of the lack of production of mature viral particles, owing to the fundamental role played by this protein. On the basis of the immunoprecipitation and hemadsorption assay results, however, the possibility for the concomitant involvement of virus-coded HA may not be excluded due to its incorrect or defective association or insertion into cellular plasma membrane. 59 Inhibition of multiplication of RNA genome containing viruses performed by different concentrations ofMESNA. G. Conti 1, P.Portincasa 1, F. Piazza° and C. Zini° 1 Department of Pathology and Laboratory Medicine, Microbiology Section ° Department of Otorino-Odonto-Ophthalmology, University of Parma, Gramsci 14, Parma, Italy The antiviral activity of MESNA, a thiol group compound, was evaluated in cellular monolayers infected by different strains of RNA viruses, other than Influenza virus. Furthermore, the action of the compound was preliminarly evaluated also in cells infected by DNA viruses. Whereas DNA viruses were not affected, the multiplication of RNA genome viruses was inhibited at different extent, depending on the virus strains. MESNA was able to inhibit viral multiplicaton in a dose-dependent fashion and virus yield was reduced at concentrations of MESNA which did not damage mock-infected cells. With respect to influenza virus, MESNA treatment determined a marked reduction of the normal synthesis of early and late virus-induced proteins suggesting an action on viral RNA transcriptase activity. However, “in vitro” assay of viral RNA dependent-RNA polymerase activity performed on purified virions showed negative results in that MESNA was not able to inhibit or block “in vitro” viral enzyme activity. This evidence led us to hypothesise a possible role of a cellular factor (s) interacting with a function (s) expressed by the virus working during the early phase of infection. Data obtained with human influenza virus strain, A, NWS, H1N1, were reproducible and comparable with those obtained with avian influenza virus strain, A, Ulster 73, H7N1. Furthermore, data obtained in MDCK cells were comparable to those, above described, obtained in LLC-MK2 cells.

Therapeutic Activity of an Anti-Idiotypic Antibody-Derived Killer Peptide against Influenza A Virus Experimental Infection / Conti, Giorgio; Magliani, Valter; Conti, Stefania; L., Nencioni; R., Sgarbanti; A. T., Palamara; Polonelli, Luciano. - (2009). (Intervento presentato al convegno 9th NATIONAL CONGRESS OF THE SIV tenutosi a ORVIETO nel 7-9 SEPTEMBER 2009).

Therapeutic Activity of an Anti-Idiotypic Antibody-Derived Killer Peptide against Influenza A Virus Experimental Infection

CONTI, Giorgio;MAGLIANI, Valter;CONTI, Stefania;POLONELLI, Luciano
2009-01-01

Abstract

58 Therapeutic Activity of an Anti-Idiotypic Antibody-Derived Killer Peptide against Influenza A Virus Experimental Infection. Giorgio Conti,1 Walter Magliani,1 Stefania Conti,1 Lucia Nencioni,2 Rossella Sgarbanti,2 Anna Teresa Palamara,2 and Luciano Polonelli1* Department of Pathology and Laboratory Medicine, Microbiology Section, University of Parma, Parma, Italy1, Department of Public Health Sciences, Pharmaceutical Microbiology Section, University of Rome La Sapienza, Rome, Italy2 The “in vitro” and “in vivo” activities of a killer decapeptide (KP) against influenza A virus is described, and the mechanisms of action are suggested. KP represents the functional internal image of a yeast killer toxin that proved to exert antimicrobial and anti-human immunodeficiency virus type 1 (HIV-1) activities. Treatment with KP demonstrated a significant inhibitory activity on the replication of two strains of influenza A virus in different cell lines, as evaluated by hemagglutination, hemadsorption, and plaque assays. The complete inhibition of virus particle production and a marked reduction of the synthesis of viral proteins (membrane protein and hemagglutinin, in particular) were observed at a KP concentration of 4 μg/ml. Moreover, KP administered intraperitoneally at a dose of 100 μg/mice once a day for 10 days to influenza A/NWS/33 (H1N1) virus-infected mice improved the survival of the animals by 40% and significantly decreased the viral titers in their lungs. Overall, KP appears to be the first anti-idiotypic antibody-derived peptide that displays inhibitory activity and that has a potential therapeutic effect against pathogenic microorganisms. Even if the precise molecular mechanism by which KP can interferewith viral multiplication remains to be determined, our results suggest that adsorption and fusion are not affected, as reported from studies with monoclonal Ab HC63. According to the experimental conditions adopted, in the presence of KP, appreciable reductions in the levels of viral proteins, including glycosylated forms, have been observed. In particular, M1 and HA synthesis in the late phase of viral multiplication were mainly affected. These findings support the hypothesis that the marked reduction of M1 synthesis may be the major cause of the lack of production of mature viral particles, owing to the fundamental role played by this protein. On the basis of the immunoprecipitation and hemadsorption assay results, however, the possibility for the concomitant involvement of virus-coded HA may not be excluded due to its incorrect or defective association or insertion into cellular plasma membrane. 59 Inhibition of multiplication of RNA genome containing viruses performed by different concentrations ofMESNA. G. Conti 1, P.Portincasa 1, F. Piazza° and C. Zini° 1 Department of Pathology and Laboratory Medicine, Microbiology Section ° Department of Otorino-Odonto-Ophthalmology, University of Parma, Gramsci 14, Parma, Italy The antiviral activity of MESNA, a thiol group compound, was evaluated in cellular monolayers infected by different strains of RNA viruses, other than Influenza virus. Furthermore, the action of the compound was preliminarly evaluated also in cells infected by DNA viruses. Whereas DNA viruses were not affected, the multiplication of RNA genome viruses was inhibited at different extent, depending on the virus strains. MESNA was able to inhibit viral multiplicaton in a dose-dependent fashion and virus yield was reduced at concentrations of MESNA which did not damage mock-infected cells. With respect to influenza virus, MESNA treatment determined a marked reduction of the normal synthesis of early and late virus-induced proteins suggesting an action on viral RNA transcriptase activity. However, “in vitro” assay of viral RNA dependent-RNA polymerase activity performed on purified virions showed negative results in that MESNA was not able to inhibit or block “in vitro” viral enzyme activity. This evidence led us to hypothesise a possible role of a cellular factor (s) interacting with a function (s) expressed by the virus working during the early phase of infection. Data obtained with human influenza virus strain, A, NWS, H1N1, were reproducible and comparable with those obtained with avian influenza virus strain, A, Ulster 73, H7N1. Furthermore, data obtained in MDCK cells were comparable to those, above described, obtained in LLC-MK2 cells.
2009
Therapeutic Activity of an Anti-Idiotypic Antibody-Derived Killer Peptide against Influenza A Virus Experimental Infection / Conti, Giorgio; Magliani, Valter; Conti, Stefania; L., Nencioni; R., Sgarbanti; A. T., Palamara; Polonelli, Luciano. - (2009). (Intervento presentato al convegno 9th NATIONAL CONGRESS OF THE SIV tenutosi a ORVIETO nel 7-9 SEPTEMBER 2009).
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