title: Oseltamivir Prophylaxis Reduces Inflammation and Facilitates Establishment of Cross-Strain Protective T Cell Memory to Influenza Viruses.
abstract: CD8(+) T cells directed against conserved viral regions elicit broad immunity against distinct influenza viruses, promote rapid virus elimination and enhanced host recovery. The influenza neuraminidase inhibitor, oseltamivir, is prescribed for therapy and prophylaxis, although it remains unclear how the drug impacts disease severity and establishment of effector and memory CD8(+) T cell immunity. We dissected the effects of oseltamivir on viral replication, inflammation, acute CD8(+) T cell responses and the establishment of immunological CD8(+) T cell memory. In mice, ferrets and humans, the effect of osteltamivir on viral titre was relatively modest. However, prophylactic oseltamivir treatment in mice markedly reduced morbidity, innate responses, inflammation and, ultimately, the magnitude of effector CD8(+) T cell responses. Importantly, functional memory CD8(+) T cells established during the drug-reduced effector phase were capable of mounting robust recall responses. Moreover, influenza-specific memory CD4(+) T cells could be also recalled after the secondary challenge, while the antibody levels were unaffected. This provides evidence that long-term memory T cells can be generated during an oseltamivir-interrupted infection. The anti-inflammatory effect of oseltamivir was verified in H1N1-infected patients. Thus, in the case of an unpredicted influenza pandemic, while prophylactic oseltamivir treatment can reduce disease severity, the capacity to generate memory CD8(+) T cells specific for the newly emerged virus is uncompromised. This could prove especially important for any new influenza pandemic which often occurs in separate waves.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville VIC 3010, Australia.
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Bird
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville VIC 3010, Australia.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Olson
authors.affiliation: WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory (VIDRL), at the Peter Doherty Institute for Infection and Immunity, Parkville VIC 3010, Australia; Melbourne School of Population and Global Health, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Aeron C
authors.initials: AC
authors.lastname: Hurt
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38105, United States of America.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Oshansky
authors.affiliation: WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory (VIDRL), at the Peter Doherty Institute for Infection and Immunity, Parkville VIC 3010, Australia; Federation University, School of Applied Sciences and Biomedical Sciences, Gippsland Victoria 3842, Australia.
authors.forename: Ding Yuan
authors.initials: DY
authors.lastname: Oh
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville VIC 3010, Australia; WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory (VIDRL), at the Peter Doherty Institute for Infection and Immunity, Parkville VIC 3010, Australia.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Reading
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville VIC 3010, Australia.
authors.forename: Brendon Y
authors.initials: BY
authors.lastname: Chua
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN 38105, United States of America.
authors.forename: Yilun
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN 38105, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Epidemiology and Biostatistics, University of Georgia, Athens, GA 30602, United States of America.
authors.forename: Andreas
authors.initials: A
authors.lastname: Handel
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville VIC 3010, Australia.
authors.forename: David C
authors.initials: DC
authors.lastname: Jackson
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville VIC 3010, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Turner
authors.affiliation: Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38105, United States of America.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomas
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Parkville VIC 3010, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kedzierska
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005289:Ferrets; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D053139:Oseltamivir / Q000627:therapeutic use*; D019562:Viral Load / Q000187:drug effects; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir