Scientists may have uncovered a novel approach to HIV treatment, according to the results of a new study. Writing in the current issue of the journal Molecular Cell, researchers report that increased levels of manganese in yeast cells slow the activity of a key enzyme, reverse transcriptase. In HIV, this change hampers the retrovirus's ability to generate copies of itself, effectively stalling its spread. The higher concentrations of manganese in the yeast cells stem from mutations in a gene called PMR1. Identification of the human equivalent of PMR1 and genetic regulation of manganese levels, the investigators suggest, could form the basis for a new method of fighting HIV.
HIV is an especially difficult target because it adapts so readily, often becoming resistant to previously effective treatments. For this reason, continuing the search for new ways of inhibiting HIV is critical, write Jef Boeke and colleagues at Johns Hopkins University. Retroviruses like HIV replicate by using reverse transcriptase to make new copies of DNA from RNA. Current treatments such as AZT inhibit growth by targeting the reverse transcriptase directly. But the new finding suggests another route. "These results point to a never-before-proposed way to try to stop HIV in its tracks--that simply manipulating concentrations of a metal, manganese, can have a profound effect," Boeke says. The necessary regulation could take place at the genetic level. By studying yeast, the group learned that the PMR1 protein ferries excess manganese and calcium out of the cell. When this gene isn't working properly, the extra manganese disrupts the activity of the reverse transcriptase, thus stymieing DNA production. In fact, on the basis of the yeast findings, the group suspects that the presence of even three times the normal levels of manganese could reduce the activity of HIV's reverse transcriptase by half. Therefore, once identified in humans, the manganese transporter could serve as a potential drug target.
Originally, the group intended to study yeast genetics for a better understanding of retroviruses and HIV. With regard to the possibility that their findings could lead to a new class of drug, Boeke remarks, "It was completely unexpected, but very satisfying."