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Researchers have obtained the X-ray crystal structure of a monoclonal antibody (mAb) bound to the lethal H5N1 strain of avian influenza virus A. The structure reveals that the heavy chain of the mAb inserts into a highly conserved pocket in the of the haemagglutinin protein stem. The structure shows how this insertion might inhibit the conformational change exploited by the virus to breach the host's cell membrane. It thus hints at a possible new strategy for preventing seasonal influenza as well as warding off a putative bird flu epidemic. Researchers at the Dana-Farber Cancer Institute, Burnham Institute for Medical Research, and the Centers for Disease Control and Prevention have identified human monoclonal antibodies that can neutralize a wide range of influenza A viruses, including viruses associated with previous pandemics, and some seasonal influenza viruses, and the notorious H5N1. While H5N1 is lethal it does not exist in a form transmissible between people. The inhibitory activity of the monoclonal antibodies against a range of influenza viruses bodes well for attacking mutant versions of H5N1 that possess that talent. "Our human monoclonal antibody protected mice from the lethal H5N1 virus even when injected three days after infection," says CDC's Ruben Donis, "This is good news, but many antibodies can do this. What surprised us is that the same antibody protected mice from a lethal infection with a very different virus such as the H1N1 subtype that causes seasonal human infections; this is really remarkable." Seasonal influenza causes mild and severe illness worldwide and results in 250,000 deaths annually. The best protection against seasonal influenza is a yearly vaccination against the riskiest strain. However, new viruses are emerging constantly in other animals and occasionally cross from those species to humans. Health professionals, the World Health Organization and others bodies are warning that the human race is long overdue a global influenza epidemic on a greater scale than that seen in 1918. Medical science must, therefore, investigate all possible weapons against influenza viruses. The continued spread of H5N1 across eastern Asia and other countries could ultimately represent a significant threat to human health once this virus mutates. According to Burnham's Robert Liddington, monoclonal antibodies that thwart the viral invasion are a promising weapon. Their X-ray studies reveal useful details that could help biomedical scientists develop these weapons for clinical practice. "The head portion of haemagglutinin is highly mutable, leading to the rise of forms of the virus that can evade neutralizing antibodies," explains Liddington. "However, the stem region of haemagglutinin is highly conserved because it undergoes a dramatic conformational change to allow entry of viral RNA into the host cell. It's very difficult to get a mutation that doesn't destroy that function, which explains why we aren't seeing escape mutants and why these antibodies neutralize such a variety of strains of influenza." Monoclonal antibodies are far more expensive to manufacture than small molecule drugs, such as oseltamivir, Tamiflu, an inhibitor of the viral enzyme neuraminidase. However, viruses can evolve resistance to small molecules. These changes block the drug's mode of action without crippling the virus. Focusing on highly conserved proteins may preclude an evolutionary response by the virus. The researchers suggest that, while more expensive, therapeutic antibodies can be manufactured and stockpiled so that in the event of a pandemic, they could be used in combination with antiviral drugs to contain an outbreak for the six to nine months that it takes to produce a vaccine to a new viral strain. "There are clear settings where human monoclonal antibodies can be used strategically for both the prevention and early treatment of influenza infection and disease," says team member Wayne Marasco. "At-risk individuals, such as first responders and medical personnel, exposed family members and co-workers and patients who cannot make antibodies because of pre-existing medical conditions or advanced age, could all benefit from this new type of therapy." Related links:
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