photo by Todd McNaught
They pick locks on entryway doors. They tiptoe without a trace past motion detectors. Should they trip the alarm system, a well-stocked tool kit contains whatever is needed to silence it.
Like experienced burglars attempting to steal your prized possessions, these viruses come armed to infect us. Although the human body has multiple security systems to halt unauthorized invaders in their tracks, viruses can evade capture with skill. Once safely inside the host, they can freely multiply and spread through the body, sometimes causing serious disease.
Recent research from Dr. Adam Geballe's lab in the Human Biology Division sheds new light on the evasive tactics of a common herpes virus called human cytomegalovirus (HCMV). Generally harmless to healthy individuals, HCMV can cause serious illness in people with weakened immune systems, such as transplant patients. The new findings could contribute to efforts at developing better antiviral drugs that prevent infection.
The study is published in the January issue of the Journal of Virology and was led by Dr. Stephanie Child, a staff scientist in the Geballe laboratory. Coauthors included Dr. Morgan Hakki, an infectious diseases fellow, Katherine De Niro, a research technician, and Geballe, who is also a member of the Clinical Research Division.
"Cells have amazing defense systems against attackers such as viruses," Child said. "But viruses-including human cytomegalovirus-have some pretty elegant means of countering them. Our study has identified two viral genes responsible for HCMV's ability to evade the cell's antiviral response, which helps us to better understand-and possibly interfere with-the process."
A common virus
The majority of American adults are infected with HCMV, a type of herpes virus that in most individuals causes no symptoms. In people with compromised immune systems, such as leukemia patients who have undergone stem-cell transplants, HCMV infection can cause life-threatening pneumonia or gastrointestinal disease. Infected transplant patients receive antiviral drugs to help prevent serious complications. Individuals with AIDS who are infected with HCMV often develop an eye infection known as retinitis.
Like many other viruses, HCMV infection triggers cellular defense systems to spring into action. A common strategy is for a cell to attempt to shut down its system for making proteins, the molecules that build most working parts of all organisms. Because viruses have no protein synthesis machinery of their own, they rely on the host cell's system to manufacture new viral particles using information contained in the virus' genetic blueprint.
Child said that shutting off protein synthesis is an act of sacrifice for a cell.
"Blocking protein synthesis is bad for the cell-it will die," she said. "But the body is willing to give up a few cells if it will prevent a virus from being able to multiply and ultimately spread through the body."
Despite this brute-force security system, Child said that many viruses-including other members of the herpes virus family-contain genes that can block the protein-synthesis shutoff before it starts. This enables the virus to commandeer the cell into becoming what is essentially a virus-production factory.
In a study published in 2002, the Geballe lab was the first to demonstrate that HCMV possesses this ability. Their new study focused on identifying the viral genes responsible for the evasion.
To pinpoint the genes, Child and colleagues relied on another virus called vaccinia virus, which also employs a strategy to prevent the shutoff of protein synthesis. For their experiment, they used a mutant version of the vaccinia virus incapable of preventing protein-synthesis shutoff because it lacks a necessary gene. The researchers then added small bits of HCMV DNA to the defective vaccinia virus to see whether any contained the genes that could restore the vaccinia virus' ability to interfere with protein synthesis.
Two genes, called TRS1 and IRS1, were found to counteract the critical host cell antiviral defense system. Child said that these genes, like related genes from other viruses that have been studied, interfere with the early steps of a cascade of events that ultimately lead to a shutoff of protein synthesis.
Although related in function to the counterattack strategies used by other viruses, preliminary studies suggest that TRS1 and IRS1 may have some unique features because the proteins made from these genes differ in sequence from their counterparts in other viruses.
"These are complicated proteins," Child said. "We don't yet know all the functions they can carry out."
In the long term, the research could lead to new therapies for preventing viral infection. Most of the existing drugs for treating CMV and other herpes viruses work by interfering with the ability of the virus to copy its DNA, a critical step for its reproduction. The virus may develop resistance to these medications.
"Interfering with the virus' anti-antiviral mechanism could be a great global target for a drug to attack," Child said.