This has been the second year of operation for the Emerging Viral Pathogens Section. Our work this year has focused on setting the stage to initiate studies with monkeypox virus in vitro and in vivo. Studies were significantly delayed until the facility received Select Agent registration with the Centers for Disease Control and Prevention in the third quarter of FY08. Our work may be divided into three distinct areas: 1. establishing the nonhuman primate monkeypox model at NIAID 2. developing surrogate systems for monkeypox virus as interim investigations until monkeypox virus work is allowed and 3. establishing simian hemorrhagic fever virus as a prototypical system for viral hemorrhagic fever.? ? 1. Upon granting of Select Agent approval from CDC, we initiated the process transitioning the established monkeypox virus nonhuman primate model. Characterized seed virus obtained from USAMRIID was prepared for nonhuman primate studies. Our first study established the mortality of the NIAID grown virus is phenoypically similar to our previous experience at other institutes. In addition we expanded our experience of sublethal disease and documenting the clinical and virological parameters. We will continue to perform dose seeking and novel routes to further refine the existing model. ? ? 2. In place of monkeypox virus investigations (delayed due to CDC approval) we have developed three lines of inquiry. The first is to evaluate the antiviral efficacy of Novantrone. This drug has shown antiviral efficacy against vaccinia virus and monkeypox virus. The drug will be evaluated in mice using a cowpox model. If efficacious, the drug will be further evaluated in nonhuman primates. Second, it was reported that nonhuman primates are susceptible to naturally occuring cowpox virus. Animals that became infected developed severe fatal disease. Using established parameters for our other orthopox virus nonhuman primate models we have performed serial sacrifice experiments and dose ranging experiments. These experiments suggest that cowpox does cause a pox-like disease in nonhuman primates but may not be robust enough to function as a surrogate for smallpox virus infection. ? ? 3.Simian Hemorrhagic Fever Virus (SHFV) is a member of the arterivirus family in the order Nidovirales. SHFV is classified as a BSL-2 agent as it is not infectious to humans and can therefore be used to study the pathogenesis of viral hemorrhagic fevers in a non-human primate model without BSL-4 biocontainment. SHFV was implicated as a confounding factor during an Ebola Reston virus outbreak in an animal holding facility, during that outbreak infected animals developed fatal disease 2 to 7 days after onset of clinical signs and SHFV and Ebola Reston virus could be detected The difference in pathogenesis between Rhesus macaques and African origin non-human primates allows for an in-depth study of a single pathogen with starkly contrasting disease courses depending upon the host.
The aim of this study is to establish a non-human primate model of viral hemorrhagic fever using SHFV in Rhesus macaques. Past studies of SHFV pathogenesis were performed in the 1960s, 70s and 80s before the advent of many modern techniques such as flow cytometry and reverse genetic systems. Our goal is to establish a model system for use in further studies investigating the role of the immune response, other host responses, and viral factors leading to pathogenesis. We are currently characterizing several isolates for determination of the new prototypical strain, developing reagents, and preparing the necessary regulatory documents for animal experimentation.
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