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The latest outbreak of ebolavirus in West Africa has demonstrated our public health systems' limited ability to respond to rare, highly virulent communicable diseases. Despite years of research on ebolavirus and marburgvirus, we have no vaccines or treatments available. The recent emergence of Zaire ebolavirus in West Africa 1 has come as a surprise in a region more commonly known for its endemic Lassa fever, another viral hemorrhagic fever caused by an Old World arenavirus. Yet the region has seen previous ebolavirus activity (see map). In the mid-1990s, scientists discovered Côte d'Ivoire ebolavirus (now known as Taï Forest ebolavirus ) as a cause of a single reported nonfatal case in a researcher who performed a necropsy on an infected chimpanzee. The episode initiated a major research investigation in and around the Taï Forest region — an effort that failed to . . .

SignificanceMiddle East Respiratory Syndrome, caused by the MERS coronavirus (MERS-CoV), continues to cause severe respiratory disease with a high case fatality rate. To date, potential antiviral treatments for MERS-CoV have shown limited efficacy in animal studies. Here, we tested the efficacy of the broad-acting antiviral remdesivir in the rhesus macaque model of MERS-CoV infection. Remdesivir reduced the severity of disease, virus replication, and damage to the lungs when administered either before or after animals were infected with MERS-CoV. Our data show that remdesivir is a promising antiviral treatment against MERS that could be considered for implementation in clinical trials. It may also have utility for related coronaviruses such as the novel coronavirus 2019-nCoV emerging from Wuhan, China. The continued emergence of Middle East Respiratory Syndrome (MERS) cases with a high case fatality rate stresses the need for the availability of effective antiviral treatments. Remdesivir (GS-5734) effectively inhibited MERS coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model. Here, we tested the efficacy of prophylactic and therapeutic remdesivir treatment in a nonhuman primate model of MERS-CoV infection, the rhesus macaque. Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV−induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions. Therapeutic remdesivir treatment initiated 12 h postinoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions. The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. It may also be considered for a wider range of coronaviruses, including the currently emerging novel coronavirus 2019-nCoV.

Following the Ebola virus disease epidemic in west Africa, there has been increased awareness of the need for improved therapies for emerging diseases, including viral haemorrhagic fevers such as those caused by Ebola virus and other filoviruses. Our continually improving understanding of the virus life cycle coupled with the increased availability of ‘omics’ analyses and high-throughput screening technologies has enhanced our ability to identify potential viral and host factors and aspects involved in the infection process that might be intervention targets. In this Review we address compounds that have shown promise to various degrees in interfering with the filovirus life cycle, including monoclonal antibodies such as ZMapp, mAb114 and REGN-EB3 and inhibitors of viral RNA synthesis such as remdesivir and TKM-Ebola. Furthermore, we discuss the general potential of targeting aspects of the virus life cycle such as the entry process, viral RNA synthesis and gene expression, as well as morphogenesis and budding.

The biology of the Ebola virus and the epidemiology and pathogenesis of infection, as well as management of outbreaks, are reviewed. Recent progress has been made in the development of diagnostics, vaccines, and medical treatments for this dangerous filovirus.

The COVID-19 pandemic progresses unabated in many regions of the world. An effective antiviral against SARS-CoV-2 that could be administered orally for use following high-risk exposure would be of substantial benefit in controlling the COVID-19 pandemic. Herein, we show that MK-4482, an orally administered nucleoside analog, inhibits SARS-CoV-2 replication in the Syrian hamster model. The inhibitory effect of MK-4482 on SARS-CoV-2 replication is observed in animals when the drug is administered either beginning 12 h before or 12 h following infection in a high-risk exposure model. These data support the potential utility of MK-4482 to control SARS-CoV-2 infection in humans following high-risk exposure as well as for treatment of COVID-19 patients. While vaccines protecting against SARS-CoV-2 infection are approved, currently, there are no drugs suitable for high-risk exposure use against SARS-CoV-2. Here, Rosenke et al. provide evidence that orally delivered MK-4482, a nucleoside analog, inhibits SARS-CoV-2 replication in the Syrian hamster model.

Ebola viruses are the causative agents of a severe form of viral haemorrhagic fever in man, designated Ebola haemorrhagic fever, and are endemic in regions of central Africa. The exception is the species Reston Ebola virus, which has not been associated with human disease and is found in the Philippines. Ebola virus constitutes an important local public health threat in Africa, with a worldwide effect through imported infections and through the fear of misuse for biological terrorism. Ebola virus is thought to also have a detrimental effect on the great ape population in Africa. Case-fatality rates of the African species in man are as high as 90%, with no prophylaxis or treatment available. Ebola virus infections are characterised by immune suppression and a systemic inflammatory response that causes impairment of the vascular, coagulation, and immune systems, leading to multiorgan failure and shock, and thus, in some ways, resembling septic shock.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a widely distributed hemorrhagic fever virus and the cause of hemorrhagic disease in Africa, Southern and Eastern Europe, the Middle East, India and Asia. Recent emergence of CCHFV into Spain indicates that the geographic range of this virus is expanding and the presence of its tick vector in several countries without reported disease suggest that CCHFV will continue to spread. Research into CCHFV was historically limited by a lack of suitable animal models and tools to study viral pathogenesis. However, in the past few years the toolset for studying CCHFV has expanded with small animal and non-human primate models for CCHFV being developed along with a reverse genetics system that allows for investigation of viral determinants of disease. These tools have been utilized to understand how CCHFV antagonizes host restriction factors and to develop novel vaccine candidates that may help limit the substantial morbidity and mortality in humans caused by CCHFV.

The filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with a high mortality rate in humans and nonhuman primates. Among the most-promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses a single filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). Importantly, a single injection of blended rVSV-based filovirus vaccines was shown to completely protect nonhuman primates against Marburg virus and 3 different species of Ebola virus. These rVSV-based vaccines have also shown utility when administered as a postexposure treatment against filovirus infections, and a rVSV-based Ebola virus vaccine was recently used to treat a potential laboratory exposure. Here, we review the history of rVSV-based vaccines and pivotal animal studies showing their utility in combating Ebola and Marburg virus infections.

Ebola virus (EBOV) expresses three different glycoproteins (GPs) from its GP gene. The primary product, soluble GP (sGP), is secreted in abundance during infection. EBOV sGP has been discussed as a potential pathogenicity factor, however, little is known regarding its functional role. Here, we analyzed the role of sGP in vitro and in vivo . We show that EBOV sGP has two different functions that contribute to infectivity in tissue culture. EBOV sGP increases the uptake of virus particles into late endosomes in HEK293 cells, and it activates the mitogen-activated protein kinase (MAPK) signaling pathway leading to increased viral replication in Huh7 cells. Furthermore, we analyzed the role of EBOV sGP on pathogenicity using a well-established mouse model. We found an sGP-dependent significant titer increase of EBOV in the liver of infected animals. These results provide new mechanistic insights into EBOV pathogenicity and highlight EBOV sGP as a possible therapeutic target.

A novel coronavirus that has emerged in the Middle East and that has been associated with several human deaths was shown to cause a similar disease in macaques, thus approximating Koch's postulates. To the Editor: During the past year, a newly identified human coronavirus (hCoV) associated with severe respiratory disease and occasionally acute renal failure has emerged in the Middle East. 1 A total of 15 laboratory-confirmed human cases have been reported from Saudi Arabia, Qatar, Jordan, and England, with 9 deaths. The first human isolate of hCoV-EMC/2012 1 was classified as a betacoronavirus, which placed it in the same genus as the coronavirus that causes the severe acute respiratory syndrome (SARS). 2 Studies revealed a broad tropism for replication in cell lines originating from different mammalian species, potentially indicating a low barrier for cross-species . . .