Influenza virus: a single noninfectious interferon induction-suppressing particle blocks expression of interferon-inducing particles

Abstract

The interferon (IFN)-inducing capacity of influenza virus plays a significant role in the efficacy of candidate live attenuated influenza vaccines (LAIVs). IFN is induced by a subpopulation of noninfectious biologically active particles (niBAPs) that can be defined and quantified as IFN-inducing particles (IFPs). When chicken embryonic cells were infected with increasing multiplicities of IFP (m(ifp)), the amount of IFN produced was that expected from a Poisson distribution of cells infected with ≥1 IFP. Problematically, some isolates of influenza virus induced less IFN than expected at higher m(ifp). We postulated that these stocks contained another subpopulation of niBAP, IFN induction-suppressing particles (ISPs). A single ISP was assumed capable of preventing IFN production completely in cells coinfected with IFP. Virus stocks were reconstructed to contain a wide range of ratios of IFP:ISP and used to generate IFN-induction dose-response curves. The deviation of the observed yields of IFN from those expected if the virus stock consisted only of IFP fits well the results expected from a formulation of the Poisson distribution that provides the fraction of IFP-infected cells expected to become coinfected with ISP, and hence not yield IFN, as the ratio IFP:ISP decreases. The ideal LAIV might be thought to contain little or no ISP so as to maximize IFN production; however, the most effective LAIV appear to regulate the production of IFN. Thus, it is possible that an optimal ratio of IFP:ISP may exist to produce more effective LAIV, an event that may sometimes occur in nature, or be reconstructed.