Feb. 21, 2008 The HIV-1 virus cripples the human immune system by targeting white blood cells called T cells that form the body’s first line of defense in fighting infections. A recent study by researchers from the University of Massachusetts Amherst shows that a protein found in the saliva of deer ticks prevents the HIV-1 virus from attaching to the surface of T cells, which is the critical first step in the virus’ attack strategy.
Since the protein suppresses the action of T cells, it may also prove to be an effective treatment for autoimmune diseases like asthma and multiple sclerosis caused by an overactive immune system that mounts an attack against the body’s own cells and tissues, and it could be useful to suppress the immune system to prevent the rejection of transplanted organs.
When the HIV-1 virus enters a human host, it attaches to the surface of T cells before fusing with the cell membrane and injecting its DNA into the nucleus. “This allows the virus to use the machinery of the T cell to copy itself and multiply,” says Juan Anguita of the UMass Amherst department of veterinary and animal sciences. “Deer ticks, which are carriers of Lyme disease, produce a protein that can interfere with the initial attachment of the HIV-1 virus, which could lead to new treatments that stop the infection process before it begins.” Additional members of the research team include Ignacio Juncandella, Tonya Bates and Elias Olivera of veterinary and animal sciences.
Deer tick saliva contains the protein Salp15, which stops T cells from activating by binding to a specific site on their surface called the CD4 receptor. Since T cells initiate the body’s immune response to invading viruses and bacteria, this strategy allows the tick to evade a host’s immune system as it feeds for up to seven days. As it turns out, the CD4 receptor is also the site used by the HIV-1 virus to attach to T cells.
“Salp15 binds to proteins in the CD4 receptor that are furthest from the cell membrane in both mouse and human cells,” says Anguita. “This region overlaps with the binding region used by a protein on the envelope of the HIV-1 virus called gp120, making Salp15 one of several potential molecules being studied as entry-targeting inhibitors.”
Laboratory studies showed that the presence of Salp15 could inhibit the attachment of HIV-1 by almost 70 percent at the highest concentration tested. This effect may result from changes in the shape of the CD4 receptor caused by the binding of Salp15. Additional studies showed that Salp15 was also able to bind gp120, making it unable to attach to the CD4 receptor.
Since gp120 can only attach to one site on the CD4 receptor, and its shape has to fit exactly into the receptor’s proteins, this interaction is as specific as opening a lock with a key. Salp15 changes the shape of the key and the lock, preventing the system from working.
Anguita and Juncandella were also part of a study performed in cooperation with the Vermont Lung Center and the University of Vermont showing that Salp15 inhibited the development of asthma in mice. The researchers induced asthma in a group of mice that also received Salp15 and compared them to a control group. Mice that received Salp15 had airways that were less reactive, and showed lower levels of several biochemical markers that indicate a T cell response. Results were published in June 2007 in The Journal of Immunology.
“The activation of T Cells is necessary for the development of allergic airway disease in mice, which shares many features of human allergic asthma,” says Anguita. “Effectively controlling the activities of these cells could be a panacea for asthma therapy.”
Anguita believes that Salp15 may lead to treatments for HIV-1, transplant rejection and autoimmune diseases with fewer side effects than traditional medications like steroids and protease inhibitors, partly because its action is so specific. “HIV-1 and transplant patients are on powerful medications for life, and most of these have secondary effects like nerve damage and liver problems, says Angiuta. “This makes the development of new treatments an important area of research.”
Results were published in the February 2008 issue of Biochemical and Biophysical Research Communications.
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