Lassa virus causes a hemorrhagic fever endemic in West Africa. The pathogenesis and the immune responses associated with the disease are poorly understood, and no vaccine is available. We followed virological, pathological, and immunological markers associated with fatal and nonfatal Lassa virus infection of cynomolgus monkeys. The clinical picture was characterized by fever, weight loss, depression, and acute respiratory syndrome. Transient thrombocytopenia and lymphopenia, lymphadenopathy, splenomegaly, infiltration of mononuclear cells, and alterations of the liver, lungs, and endothelia were observed. Survivors exhibited fewer lesions and a lower viral load than nonsurvivors. Although all animals developed strong humoral responses, antibodies appeared more rapidly in survivors and were directed against GP 1 , GP 2 , and NP. Type I interferons were detected early after infection in survivors but only during the terminal stages in fatalities. The mRNAs for CXCL10 (IP-10) and CXCL11 (I-TAC) were abundant in peripheral blood mononuclear cells and lymph nodes from infected animals, but plasma interleukin-6 was detected only in fatalities. In survivors, high activated-monocyte counts were followed by a rise in the total number of circulating monocytes. Activated T lymphocytes circulated in survivors, whereas T-cell activation was low and delayed in fatalities. In vitro stimulation with inactivated Lassa virus induced activation of T lymphocytes from all infected monkeys, but only lymphocytes from survivors proliferated. Thus, early and strong immune responses and control of viral replication were associated with recovery, whereas fatal infection was characterized by major alterations of the blood formula and, in organs, weak immune responses and uncontrolled viral replication.

A predominantly pig-to-human zoonotic infection caused by the novel Nipah virus emerged recently to cause severe morbidity and mortality in both animals and man. Human autopsy studies showed the pathogenesis to be related to systemic vasculitis that led to widespread thrombotic occlusion and microinfarction in most major organs especially in the central nervous system. There was also evidence of extravascular parenchymal infection, particularly near damaged vessels A recent outbreak of a novel paramyxovirus subsequently named Nipah virus (NiV) infected hundreds of patients in Malaysia causing severe morbidity and a mortality rate of ϳ40%.

Nipah virus, a member of the paramyxovirus family, was first isolated and identified in 1999 when the virus crossed the species barrier from fruit bats to pigs and then infected humans, inducing an encephalitis with up to 40% mortality. At present there is no prophylaxis for Nipah virus. We investigated the possibility of vaccination and passive transfer of antibodies as interventions against this disease. We show that both of the Nipah virus glycoproteins (G and F) when expressed as vaccinia virus recombinants induced an immune response in hamsters which protected against a lethal challenge by Nipah virus. Similarly, passive transfer of antibody induced by either of the glycoproteins protected the animals. In both the active and passive immunization studies, however, the challenge virus was capable of hyperimmunizing the vaccinated animals, suggesting that although the virus replicates under these conditions, the immune system can eventually control the infection.

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 ...