In the quest to cure HIV, scientists must address an annoying feature of the virus. HIV hides in immune cells and remains there in a dormant state. HIV medication keeps the virus under control, but as soon as a person stops taking the medication, the virus reemerges.
So to get the virus out of the body completely, it must first be awakened. Then the immune system can recognize and clean up the cells in which HIV is hiding.
Researchers at Erasmus MC now show that a drug against parasites can possibly play a role in this. The drug in question is pyrimethamine, which is used, for example, to treat the infectious disease toxoplasmosis. Treatment with pyrimethamine awakens the virus from its dormant state, internist-infectiologist Henrieke Prins and molecular virologists Raquel Crespo and Cynthia Lungu discovered.
The study, published in Science Advances, involved 28 people living with HIV. The scientists divided the participants into four groups: one group received pyrimethamine, one group received another drug that the researchers expected would awaken the virus, one group received both drugs and the last group received nothing. The treatment lasted two weeks and was in addition to standard HIV medication.
In people in the group given pyrimethamine, the researchers saw evidence that the virus awoke from its dormant state. The second drug called valproic acid did not, nor did it enhance the effect of pyrimethamine. The latter was unexpected. ‘We had expected, after experiments in the laboratory, that the two drugs would reinforce each other’, Prins says.
So pyrimethamine awakens the virus, but it does not reduce the number of body cells with the dormant virus. Scientists call this the HIV reservoir. ‘Our hypothesis was that the immune system would notice and clear the awakened virus. So it turns out that doesn’t happen. The HIV reservoir remains the same’, Lungu said. ‘Another intervention may be needed to actually make the reservoir smaller’, Crespo adds.
Follow-up studies must show what pyrimethamine should be combined with to permanently remove the virus from the body. ‘It also remains to be seen whether pyrimethamine works the same way in all people with HIV since this study involved mainly white males,’ Lungu says.
‘We are proud that an inexpensive, widely used, and safe drug shows promising results’
The researchers are pleased with their results but guard against too much optimism. ‘We are proud that our study shows that an inexpensive, widely used, and safe drug shows promising results in awakening the virus. But the road to curing HIV is still long. It is very difficult to say how long that will take’, Crespo said.
The project is a textbook example of what is called bench-to-bedside research. It began with the laboratory discovery of a protein complex involved in keeping HIV asleep. Then pyrimethamine emerged from screening as a substance that can inhibit this protein complex. That eventually led to the design of this first clinical trial of the drug combination in people with HIV.
Several areas of expertise also came together in the study itself. Prins: ‘For example, the hospital pharmacy of Erasmus MC: they set up their own assay to measure the pyrimethamine concentration in the blood. We are now the only ones in the Netherlands who can do this.’
EHEG: together against HIV
This research is part of the Erasmus MC HIV Eradication Group (EHEG), in which scientists from different departments and disciplines join forces to eradicate HIV.