scholarly journals Predominance of HLA-Restricted Cytotoxic T-Lymphocyte Responses to Serotype-Cross-Reactive Epitopes on Nonstructural Proteins following Natural Secondary Dengue Virus Infection

1998 ◽  
Vol 72 (5) ◽  
pp. 3999-4004 ◽  
Author(s):  
Anuja Mathew ◽  
Ichiro Kurane ◽  
Sharone Green ◽  
Henry A. F. Stephens ◽  
David W. Vaughn ◽  
...  
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
T Lymphocyte ◽  
Mononuclear Cells ◽  
Cytotoxic T Lymphocyte ◽  
Nonstructural Proteins ◽  
Dengue Virus Infection ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Lymphocyte Responses

ABSTRACT We examined the memory cytotoxic T-lymphocytic (CTL) responses of peripheral blood mononuclear cells (PBMC) obtained from patients in Thailand 12 months after natural symptomatic secondary dengue virus infection. In all four patients analyzed, CTLs were detected in bulk culture PBMC against nonstructural dengue virus proteins. Numerous CD4+ and CD8+ CTL lines were generated from the bulk cultures of two patients, KPP94-037 and KPP94-024, which were specific for NS1.2a (NS1 and NS2a collectively) and NS3 proteins, respectively. All CTL lines derived from both patients were cross-reactive with other serotypes of dengue virus. The CD8+ NS1.2a-specific lines from patient KPP94-037 were HLA B57 restricted, and the CD8+ NS3-specific lines from patient KPP94-024 were HLA B7 restricted. The CD4+ CTL lines from patient KPP94-037 were HLA DR7 restricted. A majority of the CD8+ CTLs isolated from patient KPP94-024 were found to recognize amino acids 221 to 232 on NS3. These results demonstrate that in Thai patients after symptomatic secondary natural dengue infections, CTLs are mainly directed against nonstructural proteins and are broadly cross-reactive.

scholarly journals A Cyclic Phosphoramidate Prodrug of 2′-Deoxy-2′-Fluoro-2′-C-Methylguanosine for the Treatment of Dengue Virus Infection

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
Ratna Karuna ◽  
Fumiaki Yokokawa ◽  
Keshi Wang ◽  
Jin Zhang ◽  
Haoying Xu ◽  
...  
Keyword(s):  
Virus Infection ◽  
Oral Administration ◽  
Dengue Virus ◽  
Mononuclear Cells ◽  
Pulmonary Inflammation ◽  
Hcv Rna ◽  
Dengue Virus Infection ◽  
Peripheral Blood Mononuclear ◽  
Adverse Effect Level

ABSTRACT Monophosphate prodrug analogs of 2′-deoxy-2′-fluoro-2′-C-methylguanosine have been reported as potent inhibitors of hepatitis C virus (HCV) RNA-dependent RNA polymerase. These prodrugs also display potent anti-dengue virus activities in cellular assays although their prodrug moieties were designed to produce high levels of triphosphate in the liver. Since peripheral blood mononuclear cells (PBMCs) are among the major targets of dengue virus, different prodrug moieties were designed to effectively deliver 2′-deoxy-2′-fluoro-2′-C-methylguanosine monophosphate prodrugs and their corresponding triphosphates into PBMCs after oral administration. We identified a cyclic phosphoramidate, prodrug 17, demonstrating well-balanced anti-dengue virus cellular activity and in vitro stability profiles. We further determined the PBMC concentration of active triphosphate needed to inhibit virus replication by 50% (TP50). Compound 17 was assessed in an AG129 mouse model and demonstrated 1.6- and 2.2-log viremia reductions at 100 and 300 mg/kg twice a day (BID), respectively. At 100 mg/kg BID, the terminal triphosphate concentration in PBMCs exceeded the TP50 value, demonstrating TP50 as the target exposure for efficacy. In dogs, oral administration of compound 17 resulted in high PBMC triphosphate levels, exceeding the TP50 at 10 mg/kg. Unfortunately, 2-week dog toxicity studies at 30, 100, and 300 mg/kg/day showed that “no observed adverse effect level” (NOAEL) could not be achieved due to pulmonary inflammation and hemorrhage. The preclinical safety results suspended further development of compound 17. Nevertheless, present work has proven the concept that an efficacious monophosphate nucleoside prodrug could be developed for the potential treatment of dengue virus infection.

scholarly journals Bystander Target Cell Lysis and Cytokine Production by Dengue Virus-Specific Human CD4+ Cytotoxic T-Lymphocyte Clones

1999 ◽  
Vol 73 (5) ◽  
pp. 3623-3629 ◽  
Author(s):  
Susan J. Gagnon ◽  
Francis A. Ennis ◽  
Alan L. Rothman
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
T Lymphocyte ◽  
Hepg2 Cells ◽  
Fas Ligand ◽  
Cytokine Production ◽  
Cytotoxic T Lymphocyte ◽  
Target Cells ◽  
Dengue Virus Infection ◽  
Antigen Presenting

ABSTRACT Dengue hemorrhagic fever, the severe form of dengue virus infection, is believed to be an immunopathological response to a secondary infection with a heterologous serotype of dengue virus. Dengue virus capsid protein-specific CD4+ cytotoxic T-lymphocyte (CTL) clones were shown to be capable of mediating bystander lysis of non-antigen-presenting target cells. After activation by anti-CD3 or in the presence of unlabeled antigen-presenting target cells, these clones could lyse both Jurkat cells and HepG2 cells as bystander targets. Lysis of HepG2 cells suggests a potential role for CD4+ CTL in the liver involvement observed during dengue virus infection. Three CD4+ CTL clones were demonstrated to lyse cognate, antigen-presenting target cells by a mechanism that primarily involves perforin, while bystander lysis occurred through Fas/Fas ligand interactions. In contrast, one clone used a Fas/Fas ligand mechanism to lyse both cognate and bystander targets. Cytokine production by the CTL clones was also examined. In response to stimulation with D2 antigen, CD4+ T-cell clones produced gamma interferon, tumor necrosis factor alpha (TNF-α) and TNF-β. The data suggest that CD4+ CTL clones may contribute to the immunopathology observed upon secondary dengue virus infections through direct cytolysis and/or cytokine production.

Traditional Acupuncture Increases the Content of Beta-Endorphin in Immune Cells and Influences Mitogen Induced Proliferation

1991 ◽  
Vol 19 (02) ◽  
pp. 101-104 ◽  
Author(s):  
Mauro Bianchi ◽  
Edda Jotti ◽  
Paola Sacerdote ◽  
Alberto E. Panerai
Keyword(s):  
Immune Responses ◽  
T Lymphocyte ◽  
Peripheral Blood Mononuclear Cells ◽  
Immune Cells ◽  
Lymphocyte Proliferation ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Beta Endorphin ◽  
T Lymphocyte Proliferation ◽  
Blood Mononuclear Cells

We measured beta-endorphin concentrations in peripheral blood mononuclear cells and mitogen-induced T-lymphocyte proliferation in patient who underwent treatment with traditional acupuncture. Traditional acupuncture increased both the concentrations of the opioid in the immune cells and lymphocyte proliferation. Our data are consistent with the hypothesis that traditional acupuncture modulates immune responses in man.

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