Nipah virus (NiV) and Hendra virus (HeV) are emerging zoonotic paramyxoviruses capable of causing fatal diseases in animals and humans. NiV and HeV are unusual among the paramyxoviruses in their ability to infect and cause potentially fatal disease in a number of host species, including humans. These viruses cause viremia and systemic infections in the host, and the incubation period in animals and humans is relatively long (several days to weeks). HeV was identified first and isolated from cases of severe respiratory disease that fatally affected both horses and man. Subsequent to that appearance, an outbreak of severe febrile encephalitis associated with human deaths was reported in Malaysia, and follow-up studies identified a Hendra-like virus, now known as NiV, as the etiologic agent of that episode. NiV and HeV are biological safety level-4 (BSL4) pathogens that possess several biological features which make them highly adaptable for their use as biowarfare agents; they can be readily grown in cell culture or embryonated chicken eggs, produce high un-concentrated titers near 1x10/8 TCID50/ml, are highly infectious and transmitted via the respiratory tract, are amplified and spread in livestock serving as a source for transmission to humans, and recent evidence has also indicated that nosocomial transmissibility is possible. The development of effective therapies or vaccines for these agents is critical. We have been extensively studying the fusion and entry mechanisms of both NiV and HeV. Recently, we have identified and produced potent anti-viral peptide-based inhibitors for these viruses which block the virus-mediated membrane fusion process in recombinant assays as well as block live NiV and HeV infection in cell culture. These peptides are derived from the carboxyl (C)-terminal alpha-helical heptad repeat region of the NiV and HeV fusion glycoprotein (F), and block the virus-mediated fusion step by interfering with the formation of a trimer-of-hairpins structure in the fusion glycoprotein, which has been similarly demonstrated in a number of viral systems that possess a pH-independent mode of membrane fusion. In the absence of any passive or active immunization procedures or products to either NiV or HeV, as well as no available or effective anti-viral drugs for paramyxoviruses in general; the anti-viral peptides we have developed may well represent an effective therapy for NiV or HeV infection resulting from their use as a biological weapon, a natural outbreak, or a BSL4 laboratory accident. We hypothesize that the use of these heptad peptides will be an effective therapeutic treatment for both NiV or HeV infection in animals and humans, such that acute encephalitic disease or death, may be prevented. We will establish the required experimental conditions and parameters and test this hypothesis in a NiV infection model using the cat.
NIH ExPorter
NIH ExPorter