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Antigenic variation is a strategy exploited by influenza viruses to promote survival in the face of the host adaptive immune response and constitutes a major obstacle to efficient vaccine development. Thus, variation in the surface glycoproteins hemagglutinin and neuraminidase is reflected by changes in susceptibility to antibody neutralization. This has led to the current view that antibody-mediated selection of influenza A viruses constitutes the basis for annual influenza epidemics and periodic pandemics. However, infection with this virus elicits a vigorous protective CD8+ cytotoxic T lymphocyte (CTL) response, suggesting that CD8+ CTLs might exert selection pressure on the virus. Studies with influenza A virus–infected transgenic mice bearing a T cell receptor (TCR) specific for viral nucleoprotein reveal that virus reemergence and persistence occurs weeks after the acute infection has apparently been controlled. The persisting virus is no longer recognized by CTLs, indicating that amino acid changes in the major viral nucleoprotein CTL epitope can be rapidly accumulated in vivo. These mutations lead to a total or partial loss of recognition by polyclonal CTLs by affecting presentation of viral peptide by class I major histocompatibility complex (MHC) molecules, or by interfering with TCR recognition of the mutant peptide–MHC complex. These data illustrate the distinct features of pulmonary immunity in selection of CTL escape variants. The likelihood of emergence and the biological impact of CTL escape variants on the clinical outcome of influenza pneumonia in an immunocompetent host, which is relevant for the design of preventive vaccines against this and other respiratory viral infections, are discussed.

ABSTRACTDuring influenza virus infection innate and adaptive immune defenses are activated to eliminate the virus and thereby bring about recovery from illness. Both arms of the adaptive immune system, antibody neutralization of free virus and termination of intracellular virus replication by antiviral cytotoxic T cells (CTLs), play pivotal roles in virus elimination and protection from disease. Innate cytokine responses, such as alpha/beta interferon (IFN-a/ß) or IFN-?, can have roles in determining the rate of virus replication in the initial stages of infection and in shaping the initial inflammatory and downstream adaptive immune responses. The effect of these cytokines on the replication of pneumotropic influenza A virus in the respiratory tract and in the regulation of adaptive antiviral immunity was examined after intranasal infection of mice with null mutations in receptors for IFN-a/ß, IFN-?, and both IFNs. Virus titers in the lungs of mice unable to respond to IFNs were not significantly different from congenic controls for both primary and secondary infection. Likewise the mice were comparably susceptible to X31 (H3N2) influenza virus infection. No significant disruption to the development of normal antiviral CTL or antibody responses was observed. In contrast, mice bearing the disrupted IFN-a/ß receptor exhibited accelerated kinetics and significantly higher levels of neutralizing antibody activity during primary or secondary heterosubtypic influenza virus infection. Thus, these observations reveal no significant contribution for IFN-controlled pathways in shaping acute or memory T-cell responses to pneumotropic influenza virus infection but do indicate some role for IFN-a/ß in the regulation of antibody responses. Recognizing the pivotal role of CTLs and antibody in virus clearance, it is reasonable to assume a redundancy in IFN-mediated antiviral effects in pulmonary influenza. However, IFN-a/ß seems to be a valid factor in determining tissue tropism and replicative rates of highly virulent influenza virus strains as reported previously by others, and this aspect is discussed here.

The levels of interleukin (IL)‐1β, IL‐6, tumour necrosis factor (TNF)‐α, and macrophage inflammatory protein (MIP)‐1α released from human peripheral blood leucocytes (PBL) following interaction with influenza virus clone 7a (virulent, produces high fever in ferrets) and A/Fiji (attenuated, produces relatively low fever in ferrets) were low and similar for the two viruses. Neither strain induced interferon (IFN)‐γ, and release of IL‐8 (which occurs on incubation of PBLs alone) was reduced after interaction with the two viruses. The levels of IL‐1 and IL‐6 detected in the plasma of infected ferrets were low and did not correlate with the onset, duration or magnitude of the fevers produced by clone 7a and A/Fiji. Relatively large amounts (100,000 pg/kg) of IL‐1 and TNF‐α were needed to produce appreciable fever in rabbits, and such quantities of IL‐6 were not pyrogenic. Hence, as for previous observations, no evidence could be obtained that induction of known pyrogenic cytokines is responsible for the febrile response in influenza. The possibility that some other mediator(s) may be involved cannot be ruled out. J. Med. Virol. 52:336–340, 1997.© 1997 Wiley‐Liss, Inc.