Important first step towards designing new therapies for shingles

Oct 20 2006

A team of scientists at the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health (NIH), has identified a human protein that helps varicella-zoster virus, the cause of chickenpox and shingles, spread from cell to cell within the body.

NIAID virologist Jeffrey I. Cohen, M.D., and NIAID research fellow Qingxue Li, M.D., Ph.D., discovered that a surface protein of varicella-zoster virus attaches to a cellular protein called insulin-degrading enzyme, using it as a receptor to enter and infect cells. In the October 20, 2006 issue of the journal Cell, they also describe how interfering with this interaction inhibits the spread of virus among cells in the test tube. The discovery of this receptor is important in understanding varicella-zoster virus, say Drs. Cohen and Li.

Their finding is also an important first step towards designing new therapies for shingles. "If safe and effective ways of disrupting this interaction can be found, eventually new interventions may be developed for treating people with this painful and debilitating disease," says NIAID Director Anthony S. Fauci, M.D.

Shingles occurs only in people who have already had chickenpox. Once chickenpox has run its course, some virus remains dormant in nerve cells at the base of the brain and alongside the spinal cord. With advancing age and diminished immunity, the virus can reactivate years later and travel down the nerve cells to the skin. There it multiplies, causing the blistering rash of shingles and damaging sensory nerve endings. The rash usually heals within a few weeks, but the nerve damage sometimes causes one of the worst complications of shingles--a severe type of pain called postherpetic neuralgia, which can last for months or even years.

Shingles drugs already exist that prevent viral replication, speed healing and reduce the severity of the disease. But some people who are immunocompromised develop a disseminated infection and resistance to these drugs. "An additional drug against a completely different type of target might be useful for these people," says Dr. Cohen.

Just this year, the Food and Drug Administration licensed a shingles vaccine for people 60 and older after a large clinical trial carried out in collaboration with NIAID showed that the vaccine could reduce the expected number of shingles cases by half in this age group. Yet, says Dr. Li, some people who are the most vulnerable to shingles--people with AIDS and others who are severely immunocompromised--cannot receive the vaccine because it is made from a live virus.

The NIAID research began a few years ago when Dr. Cohen and his colleagues discovered that if they deleted a molecule called glycoprotein E on the surface of the virus, the virus lost its ability to infect human cells. This led them to reason that glycoprotein E is involved in the virus' infectivity, and it gave them a way to search for its receptor. Working with biologist Mir Ali, Ph.D., the team used glycoprotein E as a sort of hook to fish out a human protein to which it binds.

Dr. Li found that curtailing the expression of insulin-degrading enzyme within cells significantly reduced the infectivity of the virus and blocked its cell-to-cell spread. Conversely, genetically altering mouse and hamster cells to express human insulin-degrading enzyme rendered these cells more susceptible to varicella-zoster virus infection. Normally cells from hamsters and mice are resistant to the virus, which in nature only infects humans.

Drs. Li and Cohen also found that they could block the virus' cell-to-cell spread by adding compounds that prevented glycoprotein E from binding to insulin-degrading enzyme. One such compound was the common topical antibacterial ingredient bacitracin. Although the amount of bacitracin needed to effectively block the interaction in the laboratory would be too high for people to take safely, the finding suggests the new receptor might be a valid target for new shingles and chickenpox treatments.