Poly(I)-Poly(C ₁₂ U) but Not Ribavirin Prevents Death in a Hamster Model of Nipah Virus Infection

Abstract

Clinical nonrandomized trials demonstrate some efficacy for ribavirin in the treatment of patients with severe Nipah virus-induced encephalitis. We report here that EICAR, the 5-ethynyl analogue of ribavirin, and the OMP-decarboxylase inhibitors 6-aza-uridine and pyrazofurin have strong antiviral activity against Nipah virus replication in vitro. Ribavirin and 6-aza-uridine were tested further in hamsters infected with a lethal dose of Nipah virus. The activity of these small-molecule inhibitors was compared with that of the interferon inducer poly(I)-poly(C 12 U). Both ribavirin and 6-aza-uridine were able to delay but not prevent Nipah virus-induced mortality. Poly(I)-poly(C 12 U), at 3 mg/kg of body weight daily from the day of infection to 10 days postinfection, prevented mortality in 5 of 6 infected animals.A new paramyxovirus infecting humans emerged in Malaysia in 1998, causing 265 cases of encephalitis, with a mortality rate of 40% (4). This virus was called Nipah virus (NiV), and it causes symptoms ranging from banal febrile illness with headache to very severe acute encephalitis. Several of the patients who recovered from the initial infection suffered relapses of encephalitis several months or years later (31). NiV is a negative-strand RNA virus, closely related to the Hendra virus isolated in Australia in 1994 from horses and humans (28). Both viruses belong to the new genus Henipavirus, in the family Paramyxoviridae (34, 35). The natural reservoir of both viruses appears to be Pteropus bats, which eliminate the virus in their urine (5,11,13). The range of these bats extends from the Western Indian Ocean to Southeast Asia, Australia, and the Southwest Pacific Islands. Since the initial outbreak (which spread to Singapore) (22), two outbreaks of infection with NiV or a closely related virus were reported in Bangladesh and northern India in 2001 and four such outbreaks were recorded in Bangladesh in 2004 to 2005. These more recent outbreaks have revealed new epidemiological patterns, with the infection of humans through direct contact with fruit contaminated by infected bat excreta. The presence of antibodies against Nipah virus has been demonstrated in bats in Cambodia, and the virus has been isolated from one animal (17,24). During the 1998 outbreak in Malaysia, an open trial was run in which NiVinfected patients were treated with ribavirin, a nucleoside analogue active against both positive-and negative-strand RNA viruses (8, 15, 23): ribavirin treatment was reported to reduce the mortality rate by 36% (3).We recently developed a hamster model of NiV infection that reproduces the clinical manifestations observed in humans (36). This animal model has been used to evaluate a candidate vaccine and for serotherapy (9). We report here the in vitro and in vivo anti-NiV efficacy of selected molecules. MATERIALS AND METHODS Virus and cells.NiV was amplified and titrated, and the antiviral activity of the molecules was tested in the Vero E6 cell line (ATCC CRL-1586) in maintenance medium (Dulbecco's minimum ...

Development and validation of a chemiluminescent immunodetection assay amenable to high throughput screening of antiviral drugs for Nipah and Hendra virus

“…This may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions (Shakil et al, 2002) while significant teratogenic and/ or embryocidal effects have also been indicated for ribavirin (Chutaputti, 2000). However, a recent study showed that the 5 ethyl analogue of ribavarin but not ribavarin was able to prevent mortality in five of six animals in a hamster model of NiV infection (Georges-Courbot et al, 2006) suggesting that other replication inhibitors may be effective against Henipaviruses. The lack of effective therapeutic modalities for Henipaviruses, their classification as biological safety level-4 (BSL4) pathogens, and their inclusion as National Institute of Allergy and Infectious Diseases (NIAID) Category C priority pathogens make novel antiviral drug development a high priority.…”

N-(3-Cyanophenyl)-2-phenylacetamide, an effective inhibitor of morbillivirus-induced membrane fusion with low cytotoxicity

“…It is a water-soluble synthetic nucleoside with broad-spectrum antiviral properties that has been shown to be active in vitro against many viruses (Huffman et al, 1973;Gururangan et al, 1990;Honda et al, 1994;Ishii et al, 1996;Chong et al, 2001;Graci & Cameron, 2006;Elia et al, 2008). Although RBV was used as an antiviral agent during the first NiV outbreak in 1999 in Malaysia, its antiviral properties could not be confirmed in the generally accepted hamster model (Georges-Courbot et al, 2006). In the case of SSPE the treatment with inosiplex (isoprinosine), intraventricular alpha interferon and RBV, which is applied in many cases, may at best prolong the disease course (Weissbrich et al, 2003).…”

Determination of the henipavirus phosphoprotein gene mRNA editing frequencies and detection of the C, V and W proteins of Nipah virus in virus-infected cells

“…No vaccines or specific antiviral drugs are currently available for NiV. Although patients from the Malaysian outbreak who received ribavirin showed a lower mortality rate (Chong et al, 2001), ribavirin was unable to protect NiV-infected hamsters from fatal disease (Georges-Courbot et al, 2006).The genomes of NiV and HeV are 18 246 and 18 234 nt, respectively, making them significantly larger than most other paramyxoviruses, with the exceptions of rodentborne Beilong and J viruses (Jack et al, 2005;Li et al, 2006). The N, P and L proteins are required and sufficient for mini-genome replication, similar to other members of the subfamily Paramyxovirinae (Halpin et al, 2004).…”

“…No vaccines or specific antiviral drugs are currently available for NiV. Although patients from the Malaysian outbreak who received ribavirin showed a lower mortality rate (Chong et al, 2001), ribavirin was unable to protect NiV-infected hamsters from fatal disease (Georges-Courbot et al, 2006).…”