Virus's Achilles' Heel Revealed

18 February 2009 (All day)

Vienna, Austria--Scientists have made a discovery about the basic biology of the Nipah virus, which suggests that cheap, existing drugs for high blood pressure and malaria may help fight the disease. Nipah regularly strikes in rural Bangladesh and neighboring parts of India. The new insights about the deadly pathogen, announced here on 14 February at the International Meeting on Emerging Infectious Diseases and Surveillance, could lead to the first human drug studies within a year, scientists say.

Nipah, which belongs to the Paramyxoviridae family and causes encephalitis, was discovered during an outbreak in 1998 and 1999 in Malaysia and Singapore that killed 106 people and sickened 170 others (Science, 16 April 1999, p. 407). Researchers later found that Pteropus fruit bats are Nipah's most likely natural reservoir (Science, 28 July 2000 p. 518). In Bangladesh, the virus appears to spread via date palm sap, which is collected overnight in clay pots tied around the tree trunk and sold fresh in the morning. Fruit bats are known to visit the trees to feed, and their urine and feces can end up in the pots.

No vaccines or drugs against Nipah exist. But now, a group led by Robin Buckland of INSERM in Lyons, France, may have found Nipah's weak spot. Most researchers have assumed that the virus enters host cells through fusion between the cell's plasma membrane and the virus's envelope--a process that starts when a virus protein called G latches onto a host receptor called ephrinB2. But the INSERM team discovered that instead, the virus enters the cell through macropinocytosis, an ingestion process in which the cell membrane folds inward, engulfing the virus and its receptor in an intracellular vesicle.

Armed with that knowledge, the team tested out three drugs: Amiloride, which is used to treat hypertension and is known to block macropinocytosis; and the antimalarials chloroquine and hydroxychloroquine, which the team suspected might hamstring the virus because they raise the pH in intracellular compartments, including the vesicles created by macropinocytosis. In cell cultures, they found, all three drugs block viral replication efficiently. The team will start testing the drug in hamsters in a few weeks, says Olivier Pernet, a Ph.D. student in the group.

But tests in humans could begin even before the outcomes are known. "We're very excited by these results," says Stephen Luby, who studies Nipah at the International Centre for Diarrhoeal Disease Research in Bangladesh. Luby says he and others are already preparing a study protocol to try at least one of the drugs the next time Nipah strikes.

Given its high fatality rate and the fact that the drugs are quite safe, it probably would be unethical to conduct a randomized trial, in which half of the patients receive a placebo, Luby says. Instead, all of the patients that can be reached would receive treatment, he says, and their recovery rate would be compared with past experience.

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