Researchers uncover possible drug approach to attack HIV-infected cells
A drug being tested as a cancer treatment also appears to be effective in the laboratory against HIV, say medical centre researchers.
The findings suggest the drug may benefit patients by targeting infected cells without harming the healthy cells the body needs to defend itself against disease. Plans are under way to test the drug in people with HIV-infection.
HIV devastates the body’s immune system by taking over and killing a particular class of white blood cells known as CD4+ helper T cells. These cells coordinate the body’s defence against foreign invaders. Without the normal array of T cells, HIV-infected patients have weakened immune systems, leaving them susceptible to infections.
Stanford researchers have now found that low doses of the drug called motexafin gadolinium (or Gd-Tex) selectively kills HIV-infected CD4+ T cells. “Gd-Tex worked in vitro,” said Leonard Herzenberg, PhD, professor emeritus of genetics and senior author of the study reported in the 18th February issue of the Proceedings of the National Academy of Sciences. “It selectively killed the HIV-infected cells when they were in a mixture with healthy white blood cells. And to our surprise, only the infected CD4+ T cells were killed.”
Gd-Tex is now being tested in humans as a cancer treatment. The drug acts by accumulating in tumour cells and attacking the molecules that normally protect the cells from one type of stress. The cells therefore die more readily during radiation treatment.
When Herzenberg and his wife, Leonore Herzenberg, PhD, professor of genetics, learned about Gd-Tex, they had a hunch that the drug might also be effective in controlling HIV. Earlier studies had shown that the HIV virus attacks the cell’s natural defences against harmful molecules by reducing levels of a protective molecule called glutathione. When glutathione drops below a certain level, the weakened cell gives in to the stress and dies. Because HIV-infected cells are already under stress, additional stress induced by Gd-Tex could be enough to push weakened cells over the edge, the Herzenbergs reasoned.
To test the hypothesis, graduate student Omar Perez, primary author of the study, began treating HIV-infected blood samples with Gd-Tex. He then scanned individual cells and found that high levels of Gd-Tex were toxic to all T cells because of the attack on glutathione. Lower levels of Gd-Tex, on the other hand, were fatal only to HIV-infected CD4+ T cells.
“The first clue that Gd-Tex worked was that the CD4+ T cells were disappearing,” said Perez. Subsequent work showed that the CD4+ T cells were committing a kind of “cell suicide.” Since other blood cells were not as compromised by the HIV infection, they survived at the low doses of Gd-Tex that were fatal to HIV-infected helper T cells.
The drug’s effectiveness for HIV treatment remains an open question, and the Stanford team plans to proceed with caution. “We want to be careful in a clinical trial and start with a low dose,” said Herzenberg. For the drug to work as an HIV therapy, infected cells would have to take up Gd-Tex in an amount sufficient to kill them in patients, he said. In addition, the drug may have other ill effects. Herzenberg cautioned that the rapid destruction of infected CD4+ T cells could release harmful toxins into the body, and further testing will be required to know for sure.
Andrew Zolopa, MD, director of the Stanford Positive Care Clinic (which focuses on HIV/AIDS), is coordinating with the Herzenbergs and Pharmacyclics, California based pharmaceutical company that makes Gd-Tex, to begin clinical trials of the drug in HIV patients. They anticipate the trials will begin within the next few months