Pathogenesis of 1918 Pandemic and H5N1 Influenza Virus Infections in a Guinea Pig Model: Antiviral Potential of Exogenous Alpha Interferon To Reduce Virus Shedding

Although highly pathogenic avian influenza H5N1 viruses have yet to acquire the ability to transmit efficiently among humans, the increasing genetic diversity among these viruses and continued outbreaks in avian species underscore the need for more effective measures for the control and prevention of human H5N1 virus infection. Additional small animal models with which therapeutic approaches against virulent influenza viruses can be evaluated are needed. In this study, we used the guinea pig model to evaluate the relative virulence of selected avian and human influenza A viruses. We demonstrate that guinea pigs can be infected with avian and human influenza viruses, resulting in high titers of virus shedding in nasal washes for up to 5 days postinoculation (p.i.) and in lung tissue of inoculated animals. However, other physiologic indicators typically associated with virulent influenza virus strains were absent in this species. We evaluated the ability of intranasal treatment with human alpha interferon (-IFN) to reduce lung and nasal wash titers in guinea pigs challenged with the reconstructed 1918 pandemic H1N1 virus or a contemporary H5N1 virus. IFN treatment initiated 1 day prior to challenge significantly reduced or prevented infection of guinea pigs by both viruses, as measured by virus titer determination and seroconversion. The expression of the antiviral Mx protein in lung tissue correlated with the reduction of virus titers. We propose that the guinea pig may serve as a useful small animal model for testing the efficacy of antiviral compounds and that -IFN treatment may be a useful antiviral strategy against highly virulent strains with pandemic potential. Since 2003, influenza A viruses of the H5N1 subtype have caused devastating outbreaks in poultry in Asia, Africa, and Europe, resulting in over 400 human infections, with an overall case fatality rate of 60% (1). The increasing persistence and genetic diversity of H5N1 viruses in poultry with concomitant human infection indicate that H5N1 viruses remain a pandemic threat (3). Despite evidence for limited human-to-human transmission, these viruses have yet to exhibit sustained transmission among humans (30, 50, 77). If H5N1 viruses were to acquire this ability, the resulting pandemic could be unusually severe, requiring multiple control measures to limit the morbidity and mortality associated with a pandemic virus. Vaccination remains the primary method of reducing the morbidity associated with seasonal influenza virus infection. Due to the diversity in circulating H5N1 viruses and the overall timeline for manufacturing, antigenically well-matched vaccines may not be available in the initial stages of an H5N1 pandemic (67, 69).