Achilles' heel of the herpes virus
Researchers at the University of Michigan discovered a receptor that appears to function as one "lock" that herpes simplex virus ( HSV ) opens to allow it to enter human cells.
They've also found the gene that controls the production of that receptor, deciphered some aspects of the receptor's structure, and developed a pig-cell system that could be used to test new anti-herpes drugs.
The findings may help explain why the oral and genital herpes virus has such a successful track record.
The receptor, dubbed B5, is made by most cells for another purpose not yet understood.
HSV appears to have evolved a way to latch onto it, and fool the cell into letting the virus in. And since most cells express the gene for the B5 receptor, this may be a reason HSV can get into most kinds of cells.
" This may be one central part of the Achilles' heel in interactions of herpes virus with a cell to start infection. We can use the receptor molecule to try to understand the process and perhaps combat infection at this vulnerable site," says A. Oveta Fuller, the leader of the U-M team. " While we're still a few years away from being able to use this new knowledge to find effective drug candidates, this is a very exciting confluence of discoveries."
" It appears that B5 is a new class of viral receptor. Unlike other viruses so far, HSV seems to have evolved to take advantage of a broadly present cellular protein that has properties like that of known cellular fusion machinery," says Fuller. " No other virus has been shown to use a cellular fusion protein for entry into cells."
The gene that encodes B5 had been sequenced, but not characterized, as part of the Human Genome Project.
Discovering its role and studying the HSV entry mechanism was tricky and near impossible until Fuller's team discovered a type of pig kidney cell that isn't vulnerable to infection by human herpes virus.
They searched the genome library to find genes essential to HSV infection, isolated the B5-coding sequence, and figured out how to get pig cells to express the human B5 protein to allow the pig cells to be infected with human herpes virus.
The researchers were able to show that by placing only the DNA sequence that encodes B5 into HSV-resistant pig cells, they could make the pig cells susceptible to HSV. They were also able to block viral infection of both human cells and susceptible pig cells by adding to cell cultures a synthetic peptide made to mimic the structure of a smaller region of the B5 receptor. This peptide looks like a functional region of B5 and apparently interferes with virus engaging of the cell receptor.
The B5 molecule appears to form a shape called a coiled coil. This structure may be similar to the structure of some fusion proteins of viruses and also to cellular proteins called SNAREs.
SNARE proteins help cells to manage the fusion of membranes of vesicles inside the cell with other specific vesicles. Vesicles are tiny membrane-encased packets that encapsulate neurotransmitters, enzymes or other important substances and allow them to be transported within and between cells.
The researchers were able to show that B5 sits in the cell membrane with one end of the protein exposed outside of the cell ready to link up with viruses -- or to serve the receptor's "real" function, which still remains to be discovered. They also showed that HSV does not enter into pig cells that have an altered human B5 protein that is changed by mutations that affect a functional region important to forming a coiled coil.
" If B5 is a SNARE-like cell fusion receptor", Fuller says, "it may turn out to be useful for more than HSV drug treatment. It could act as a way to link vesicles containing drugs with cells, and deliver them inside".
The findings suggest that B5 or its viral ligand could be a target for antiviral treatment, much like cell receptors for the entry of human immunodeficiency virus ( HIV ) into cells have become targets for new AIDS drugs.
Source: University of Michigan Health System, 2005
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