A naturally occurring protein may provide a safe harbor to the virus that causes AIDS by acting as a barrier to prevent the newest medications from reaching the virus, Vanderbilt University Medical Center researchers have found.
The finding raises hope that the effectiveness of protease inhibitors could be boosted by combining the anti-HIV drugs with medication to block the action of the protein protecting the virus.
That strategy might also reduce the cost of the now-very-expensive therapy by reducing the dose needed to get enough of the drugs into the bloodstream, where it can attack HIV.
"Protease inhibitors work very well and have resulted in many patients becoming healthier," said Dr. Richard B. Kim, assistant professor of Medicine and Pharmacology.
"However, there are limitations. Not all patients do so well on the drugs. And even in those patients for whom anti-HIV therapy is very effective -- whose blood levels of HIV drop to undetectable levels using very sensitive techniques -- studies have shown that when they stop taking the drugs, the virus comes back. That means there must be sanctuaries where the virus can live and hide out."
Kim and his colleagues in the division of Clinical Pharmacology have found evidence that a "transporter molecule" called P-glyco protein (Pgp) may be creating these hide-outs. Transporter molecules protect the body from poisoning by recognizing groups of chemicals and pumping them out of cells as soon as they enter.
Their research is the subject of an article and accompanying editorial in the January 15 issue of the Journal of Clinical Investigation, published by the American Society for Clinical Investigation.
In cell cultures that express large quantities of Pgp, the VUMC researchers found that protease inhibitors were not readily absorbed by the cells.
In the body, Pgp is present in the intestines, where it prevents absorption, and in the kidneys and liver, where it promotes elimination of the chemicals it recognizes. That may help explain why the blood levels of protease inhibitors, despite administration at comparable doses, can vary so widely among individual patients, Kim said.
"Because HIV attacks the CD4-expressing lymphocytes circulating in the bloodstream, the goal of therapy would be to have an optimal level of the drug in the bloodstream so that the drug would get into to the CD4 lymphocytes and kill the virus," Kim said. "Pgp may prevent enough of the drug from getting into the bloodstream, and that may explain some of the drug failures."
Pgp is also expressed in the blood vessels lining the brain, known as the blood/brain barrier. Because HIV is known to take up residence in the brain, the researchers were interested in whether Pgp prevents protease inhibitors from crossing that barrier.
They found that when they injected protease inhibitors into mice that had been genetically engineered not to express Pgp, brain levels of the drugs climbed to seven-to-40 times higher than in mice that normally express PGP.
The researchers also found that brain levels of the protease inhibitors in normal mice were about one-tenth the blood level.
"The standard way to measure drug levels is in the blood, with the idea that if the blood level is adequate to kill the virus, we've given enough of the drug," he said. "Now the concern is that the brain level may be much lower and that the virus could escape to the brain, continue to divide there and live on."
Kim said he would next like to measure the levels of protease inhibitors in the cerebral spinal fluid of patients to determine -- at least indirectly -- whether a similar relationship exists in humans.
Another potential hide-out created by Pgp may be in some of the CD4 cells themselves, Kim said. As many as 10 percent of CD4 cells express Pgp, so it's possible that HIV is taking over those cells and stays there, protected by the cells' Pgp expression, he said.
Drugs are already available to suppress the activity of Pgp. They have been developed over the past 10-20 years because Pgp is also expressed by many cancer tumors. Pgp inhibitors have been used to boost the effectiveness of chemotherapy in these tumors.
Kim said he would like to study the effectiveness of combining protease inhibitors with Pgp inhibitors to determine if higher levels of the anti-HIV drugs can be achieved in the bloodstream and in the cerebral spinal fluid by reducing the barrier function associated with Pgp.
"This work is exciting because the potential of Pgp as a factor in drug absorption and tissue penetration has not been previously appreciated," Kim said. "We need to find out in humans how active this transporter is and whether we can inhibit its activity.
"HIV probably has multiple ways to hide out, and the one we're suggesting is that Pgp protects it from drug exposure. Ultimately, the hope is that if we can remove HIV's sanctuaries, we can begin to hope that we've killed all of the virus and that maybe we can have a cure."
Journal
Journal of Clinical Investigation