title: The administration of oseltamivir results in reduced effector and memory CD8+ T cell responses to influenza and affects protective immunity.
abstract: The clinical benefits of oseltamivir (Tamiflu) are well established, but the effects of antiviral treatment on the immune response are poorly understood. By use of flow cytometric analyses and the mouse model, we thoroughly investigated the impact of such a treatment on the immune response and the generation of protective immunity to influenza. We demonstrated that influenza-specific CD8(+) effector T cell recruitment was reduced up to 81% in the lungs of mice treated with oseltamivir (5 or 50 mg/kg twice daily; EC50 49 nM in vitro) compared to saline controls, but cell generation was unaffected in draining lymph nodes. Importantly, we showed that oseltamivir administration significantly decreased the pools of tissue-resident and circulating effector memory (93.7%) and central memory CD8(+) T cells (45%) compared to saline controls. During heterologous secondary infection, a decreased memory CD8(+) T cell pool combined with reduced generation of secondary influenza-specific effectors in the lymph nodes resulted in 10-fold decreased CD8(+) T cell recall responses, which increased mouse morbidity and delayed viral clearance. Furthermore, antiviral administration led to a significant 5.7-fold decreased production of functional anti-influenza antibodies. Thus, our study demonstrates that antiviral treatment affects the development of the adaptive immune response and protective immunity against influenza.
authors.affiliation: *Pulmonary Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Québec, Canada; and Intensive Care Unit, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Marois
authors.affiliation: *Pulmonary Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Québec, Canada; and Intensive Care Unit, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Cloutier
authors.affiliation: *Pulmonary Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Québec, Canada; and Intensive Care Unit, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Émilie
authors.initials: É
authors.lastname: Garneau
authors.affiliation: *Pulmonary Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Québec, Canada; and Intensive Care Unit, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lesur
authors.affiliation: *Pulmonary Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, Québec, Canada; and Intensive Care Unit, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec, Canada martin.richter@usherbrooke.ca.
authors.forename: Martin V
authors.initials: MV
authors.lastname: Richter
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000998:Antiviral Agents / Q000008:administration & dosage; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D007156:Immunologic Memory; D009980:Influenza A virus / Q000276:immunology*; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D053139:Oseltamivir / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D012333:RNA, Messenger; D053139:Oseltamivir
keywords: Tamiflu; adaptive immune response; antiviral; flu; immunologic consequences