Iowa City Veterans Affairs (VA) Medical Center and University of Iowa (UI) researchers have unlocked part of the mystery of how a harmless virus known as GBV-C slows the progression of HIV and prolongs survival for many patients. The report appears in the June 19 issue of The Lancet, the leading British medical journal.
The findings provide the clearest insight yet into the biological mechanisms of GBV-C, a benign cousin of the hepatitis C virus. The virus infects almost all HIV patients at some point in their illness, but seems to cause no harm by itself. When present over several years, the virus appears to slow HIV growth and keep patients from developing full-blown AIDS.
A study by the Iowa City team and other collaborators published in the March 4, 2004, New England Journal of Medicine found that 75 percent of men with persistent GBV-C infection survived at least 11 years after their HIV diagnosis, versus only 16 percent of men who were initially co-infected with GBV-C but cleared the virus over time. The men had been studied before the advent of effective HIV medications.
In the new study, the Iowa City scientists infected white blood cells with GBV-C and HIV and compared them to cells infected only with HIV. The cells with GBV-C showed an increase in certain chemokines, or immune-system proteins. These proteins bind to the same white-blood-cell receptors-molecular "docking sites"-used by HIV. When the receptors aren't available, HIV is unable to infect the cells.
When the researchers neutralized the chemokines with antibodies, GBV-C had no protective effect. HIV was free to enter host cells and proliferate.
"The next thing we have to do is determine a way to mimic the effect of this virus [GBV-C] and learn how to make it persist, so it can continue to induce these chemokines and these changes in the cell that help HIV," said senior investigator Jack Stapleton, MD of VA and UI. Lead author was Jinhua Xiang, MD, who works with Stapleton at the Iowa City VA Medical Center.
GBV-C is related to the virus that causes hepatitis C. However, it does not infect liver cells, and causes no form of hepatitis. Rather, like HIV, it infects white blood cells-specifically, helper T cells. It is also contracted in the same way as HIV-through bodily fluids. About 10 to 15 percent of healthy blood donors either have active GBV-C infection or antibodies indicating past exposure. Almost 90 percent of people with HIV, according to some studies, show evidence of having been infected with GBV-C, but about half of these patients develop antibodies that knock the virus out of their system.
GBV-C was first identified by scientists in 1995, though studies suggest it has been around since ancient times. The idea that GBV-C may delay HIV disease progression and lower mortality has been debated among AIDS scientists because of mixed research findings. Ten studies, by eight different groups of researchers, including Stapleton's, have shown improved survival or other clinical benefits among HIV patients who also have GBV-C. A few studies, though, showed no benefit.
The March 2004 study in the New England Journal of Medicine, co-authored by Stapleton and led by Carolyn Williams, PhD of the National Institute of Allergy and Infectious Diseases, was the most comprehensive GBV-C study to date. According to Stapleton, it showed that the duration of GBV-C infection may be critical in increasing survival, and this may help explain why other studies failed to find any effect.
"The survival advantage of GBV-C appears to depend on how long the GBV-C infection persists," said Stapleton, a staff physician at the Iowa City VA Medical Center and professor of medicine at UI.
According to the new findings by Stapleton and Xiang's team, GBV-C raises the blood levels of several chemokines, including one called RANTES (an acronym for "regulated on activation, normal T cell expressed and secreted"). This protein naturally occupies the same molecular docking site favored by HIV-a receptor called CCR5-and thus keeps the AIDS virus from binding to white blood cells and gaining a foothold in the body.
Drugs are under development that mimic the effect of these chemokines. However, Stapleton believes GBV-C itself should be seen as a potential HIV treatment because of its safety profile and because patients would need only a limited number of exposures to see benefits. He and his colleagues are now considering a clinical trial in which HIV patients would be infected with the virus.
"The fact that GBV-C is such a common infection, and that's it's been so extensively studied and not shown to cause any diseases, distinguishes it from other live viruses and makes it a more realistic option," said Stapleton. He pointed out that the Food and Drug Administration does not require blood donations to be screened for GBV-C, even though about 1 in 70 units of blood in the United States contains the virus.
Currently there is only one medication available, Fuzeon, that blocks HIV at the early stage of the virus' replication, before it even enters T cells. But this drug costs up to $25,000 per year and must be given by injection twice daily. Other drugs that work similarly are under development.
While many HIV patients today are helped by highly active antiretroviral therapy, or HAART, many become resistant to the drugs. Stapleton said the effect of GBV-C on HIV viral load is similar to that of HAART, though not as potent. The likelihood of resistance, however, is much lower with GBV-C.
"HIV probably doesn't become resistant to GBV-C very easily, but it is possible to lose the virus," said Stapleton. "We have to figure out how this can be prevented."
Collaborating with Stapleton and Xiang on the study were Drs. Sarah George and Sabina Wunschmann, along with Qing Chang and Donna Klinzman. The work, presented in part in 2003 at the Tenth Conference on Retroviruses and Opportunistic Infections, was funded by VA, the National Institutes of Allergy and Infectious Diseases, the UI Center for Research Enhancement, and the UI Gene Therapy Center.