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ABSTRACT: The efficacy of intravenous peramivir against influenza A (H1N1) 2009 virus infection was evaluated in mice of which immune system was suppressed by cyclophosphamide (CP) treatment. The mortality rate of the vehicle control group was 100% and the mice lost 20% of their body weight on average by day 13 post infection (p.i.). Repeated administration of peramivir (40 mg/kg once a day, intravenously for 20 days), starting at 1 h p.i., significantly reduced mortality, body weight loss, viral titers, and cytokine production in infected mice compared with the vehicle administration (p < 0.01). In addition, repeated administration of peramivir, starting at 24 h, 48 h, or 72 h p.i. also resulted in increases in survival rates and reduction of viral titers in the lungs (p < 0.01). The mean days-to-death (MDD) of the vehicle group was 14.5 days, while in the groups treated with peramivir starting at 24 h, 48 h, and 72 h p.i., the MDDs were > 23.0, 20.9, and 21.8 days, respectively. In comparison, repeated administration of oseltamivir phosphate (5 mg/kg twice a day, orally for 20 days), starting at 24 h, 48 h, and 72 h p.i., also significantly prevented body weight loss, whereas no significant differences in mortality rates and viral titers in the lungs were observed when compared with the vehicle group. These data indicated that repeated administration of peramivir was effective in promoting the survival and reducing virus replication in immunosuppressed mice infected with influenza A (H1N1) 2009 virus.
Antimicrobial Agents and Chemotherapy 03/2013; · 4.84 Impact Factor
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Mitsutaka Kitano,
Yasushi Itoh,
Makoto Kodama,
Hirohito Ishigaki,
Misako Nakayama,
Hideaki Ishida,
Kaoru Baba,
Takahiro Noda,
Kenji Sato,
Yoichiro Nihashi,
Takushi Kanazu,
Ryu Yoshida,
Ryuzo Torii,
Akihiko Sato,
Kazumasa Ogasawara
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ABSTRACT: We evaluated the efficacy of a single intravenous dose peramivir for treatment of influenza B virus infection in ferrets and cynomolgus macaques in the present study. A single dose of peramivir (60 mg/kg of body weight) given to ferrets on 1 day postinfection with influenza B virus significantly reduced median area under the curve (AUC) virus titers (peramivir, 8.3 log(10) 50% tissue culture infective doses [TCID(50)s] · day/ml; control, 10.7 log(10) TCID(50)s · day/ml; P < 0.0001). Furthermore, nasal virus titers on day 2 postinfection in ferrets receiving a single injection of peramivir (30 mg/kg) and AUCs of the body temperature increase in ferrets receiving a single injection of peramivir (30 and 60 mg/kg) were lower than those in ferrets administered oral oseltamivir phosphate (30 and 60 mg/kg/day twice daily for 3 days). In macaques infected with influenza B virus, viral titers in the nasal swab fluid on days 2 and 3 postinfection and body temperature after a single injection of peramivir (30 mg/kg) were lower than those after oral administration of oseltamivir phosphate (30 mg/kg/day for 5 days). The two animal models used in the present study demonstrated that inhibition of viral replication at the early time point after infection was critical in reduction of AUCs of virus titers and interleukin-6 production, resulting in amelioration of symptoms. Our results shown in animal models suggest that the early treatment with a single intravenous injection of peramivir is clinically recommended to reduce symptoms effectively in influenza B virus infection.
Antimicrobial Agents and Chemotherapy 08/2011; 55(11):4961-70. · 4.84 Impact Factor
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Mitsutaka Kitano,
Yasushi Itoh,
Makoto Kodama,
Hirohito Ishigaki,
Misako Nakayama,
Tomoya Nagata,
Hideaki Ishida,
Hideaki Tsuchiya,
Ryuzo Torii,
Keiko Baba,
Ryu Yoshida,
Akihiko Sato,
Kazumasa Ogasawara
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ABSTRACT: Pathogenicity of influenza B virus was examined in cynomolgus macaques to establish a macaque model suitable for vaccine and antiviral drug development. We prepared influenza B viruses for inoculation with minimal passages after isolation from patients. Macaques inoculated with influenza B virus showed higher body temperature than that before infection for 6 to 12 days. Virus was detected in nasal, tracheal, and bronchial samples until 6 days after inoculation followed by an increase in neutralizing antibody. High levels of IL-6 and TNF-α in nasal swabs from the infected macaques were correlated with fever. Symptoms and duration of the viral replication would be sufficient to evaluate efficacy of vaccines and antiviral agents. In addition, measurement of immune responses including antibody and cytokine production would provide an immunological rationale in efficacy of vaccines and antiviral agents. The results suggest that cynomolgus macaques are appropriate model animals for research of influenza B virus.
Virology 11/2010; 407(2):178-84. · 3.35 Impact Factor
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ABSTRACT: Most escape mutations have been identified on cytotoxic T lymphocyte (CTL) epitopes presented by Caucasian or African human leukocyte antigen (HLA) class I alleles, whereas a limited number of studies have identified the escape mutations on epitopes presented by Asian alleles. HLA-B54 is a common HLA allele in Asian countries. We recently identified five HLA-B*5401-restricted HIV-1-specific CTL epitopes. We here investigated escape mutations in these CTL epitopes in Japanese HIV-1-infected individuals. The frequency of substitution from Glu (E) to Asp (D) at position 7 (FV9-7D) in the Pol 154-162 (FV9) epitope was significantly higher in HLA-B*5401(+) HIV-infected individuals than in HLA-B*5401(-) individuals, whereas substitutions that were significantly higher in HLA-B*5401(+) individuals than in HLA-B*5401(-) individuals were not found in the other four epitopes. FV9-specific CTLs showed reduced killing activity against target cells pulsed with the FV9-7D mutant peptide and failed to kill those infected with the FV9-7D mutant virus, strongly suggesting that FV9-7D is an escape mutant. Furthermore, longitudinal sequence analysis of the FV9 epitope in two HLA-B*5401(+) individuals revealed that the sequence had changed from the wild type to the FV9-7D during the clinical course. Taken together, these results indicate that the FV9-7D escape mutant had been selected by FV9-specific CTLs among chronically HIV-1-infected HLA-B*5401(+) individuals.
Human immunology 11/2009; 71(2):123-7. · 2.55 Impact Factor
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ABSTRACT: HLA-B*4801 is frequently found in Asian populations but rarely in Caucasian or African populations. Although HLA-B*4801-restricted human immunodeficiency virus-1 (HIV-1) epitopes would be useful for acquired immune deficiency syndrome (AIDS) vaccine development in Asia, they have not been reported so far. In the present study, we sought to identify HLA-B*4801-restricted HIV-1 epitopes by using 17-mer overlapping peptides derived from HIV-1 Gag, Pol, and Nef as well as 8- to 11-mer truncated peptides, and thereby identified two HLA-B*4801-restricted Gag epitopes. These epitope-specific CD8(+) T cells strongly responded to HIV-1-infected cells expressing HLA-B*4801, confirming that these Gag epitopes were endogenously presented by HLA-B*4801. These epitope-specific CD8(+) T cells were elicited in five of the seven tested chronically HIV-1-infected individuals with HLA-B*4801, suggesting them to be immunodominant epitopes. These epitopes will be useful for the studies of AIDS immunopathogenesis and the development of an HIV-1 vaccine in Asia.
Human immunology 02/2009; 70(3):170-4. · 2.55 Impact Factor
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ABSTRACT: The identification of HIV-1 cytotoxic T lymphocyte (CTL) epitopes presented by each HLA allele and the characterization of their CTL responses are important for the study of pathogenesis of AIDS and the development of a vaccine against it. In the present study, we focused on identification and characterization of HIV-1 epitopes presented by HLA-B*5401, which is frequently found in the Asian population, because these epitopes have not yet been reported. We identified these epitopes by using 17-mer overlapping peptides derived from HIV-1 Gag, Pol, and Nef. Seven of these 17-mer peptides induced HLA-B*5401-restricted CD8+ T cell responses. Only five HLA-B*5401-restricted Pol- or Nef-specific CD8+ T cell responses were detected in the analysis using 11-mer overlapping peptides. Three Pol and two Nef optimal peptides were identified by further analysis using truncated peptides. These epitope-specific CTLs effectively killed HLA-B*5401-expressing target cells infected with HIV-1 recombinant vaccinia virus, indicating that these peptides were naturally processed by HLA-B*5401 in HIV-1-infected cells. These epitope-specific CD8+ T cells were elicited in more than 25% of chronically HIV-1-infected individuals carrying HLA-B*5401. Therefore, these epitopes should prove useful for studying the pathogenesis of AIDS in Asia and developing a vaccine against HIV-1.
Microbes and Infection 07/2008; 10(7):764-72. · 3.10 Impact Factor
