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Title:   Author  item
                                            PENA, LINDOMAR - University Of Marylanditem
                                            Baker, Amyitem
                                            Loving, Crystalitem
                                            Henningson, Jamieitem
                                            Lager, Kellyitem
                                            Lorusso, Alessioitem
                                            PEREZ, DANIEL - University Of Maryland
  Submitted to: Journal of Virology
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 2/23/2012
                                    Publication  Date: 5/1/2012
                                    Citation: Pena, L., Vincent, A.L., Loving, C.L., Henningson, J.N., Lager, K.M., Lorusso, A., Perez, D.R. 2012. Restored PB1-F2 into the 2009 pandemic H1N1 influenza virus has minimal effects in swine. Journal of Virology. 86(10):5523-5532.Interpretive Summary: Pigs are considered a “mixing vessel” for the generation of novel influenza viruses because they are susceptible to infection with avian and human influenza viruses. The 2009 pandemic influenza virus (pH1N1) has infected pigs in over 20 countries and several reassortants between pH1N1 and circulating influenza A viruses have been isolated, raising great concerns about the potential acquisition of virulence markers by the pH1N1 virus upon mutation or reassortment. PB1-F2 is a small protein present in some influenza viruses but absent in the 2009 pH1N1. PB1-F2 destroys immune cells and increases lung pathology in mice, but little is known about its effect in natural hosts such as the pig. In an attempt to prepare for future evolution of the pH1N1 virus and future influenza pandemics, we examined whether PB1-F2 has an effect on the replication and virulence of the pH1N1 in swine by generating PB1-F2-containing pH1N1. We found that PB1-F2 increased pH1N1 virus replication in laboratory assays. In pigs, acquisition of PB1-F2 increased the amount of virus in the lung, microscopic pneumonia, and some inflammatory responses. Our studies provide new insights into the role of PB1-F2 in pigs and underscore the impact of its acquisition for the virulence of the pH1N1 to mammalian hosts, including humans.
                                Technical Abstract: PB1-F2 is an 87-90 amino acid long protein expressed by certain influenza A viruses. Previous studies have shown that PB1-F2 contributes to virulence in the mouse model; however, its role in natural hosts - pigs, humans, or birds - remains largely unknown. Outbreaks of domestic pigs infected with the 2009 pandemic H1N1 influenza virus (pH1N1) have been detected worldwide. Unlike previous pandemic strains, pH1N1 viruses do not encode a functional PB1-F2 due to the presence of three stop codons resulting in premature truncation after codon 11. However, pH1N1s have the potential to acquire the full-length form of PB1-F2 through mutation or reassortment. In this study, we assessed whether restoring the full-length PB1-F2 ORF in the pH1N1 background would have an effect in virus replication and virulence in pigs. Restoring the PB1-F2 ORF resulted in up-regulation of viral polymerase activity at early time points in vitro and enhanced virus yields in porcine respiratory explants and in the lungs of infected pigs. There was an increase in the severity of pneumonia in pigs infected with isogenic virus expressing PB1-F2 as compared to the WT pH1N1. The extent of microscopic pneumonia correlated with increased pulmonary levels of IFN-a and IL-1ß in pigs infected with pH1N1 encoding a functional PB1-F2 but only early in the infection. Together, our results indicate that PB1-F2 in the context of pH1N1 moderately modulates viral replication, lung histopathology, and local cytokine response in pigs.


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