A team at Johns Hopkins University in the United States has reported that increasing manganese levels in cells can slow the activity of the reverse transcriptase enzyme, which HIV and other retroviruses use to convert their RNA into DNA when they attack and infect human cells. The discovery could form the basis for a new class of anti-HIV treatments. The findings appear in the April 2002 edition of Molecular Cell.
The researchers found that increased levels of manganese in yeast cells, the consequence of a defective gene called PMR1, dramatically lowered the activity of reverse transcriptase. The scientists found that HIV’s reverse transcriptase responds to increased levels of manganese in the same way. Current anti-HIV antiretroviral regimens normally include at least two drugs which target reverse transcriptase.
It was discovered that reverse transcriptase has two places where manganese and another metal, magnesium, can “dock.” If these metals are prevented from attaching themselves to reverse transcriptase, then the ability of the enzyme to work properly is disrupted. A defective gene called PMR1, was found in yeast and shown by the Johns Hopkins team to have higher concentrations of manganese and prevented the enzyme from working properly. Identification of the human form of PMR1 and genetic regulation of manganese could, the researchers postulate, form the basis for a new HIV treatment.
Having just three times more manganese than normal could cut the activity of HIV’s reverse transcriptase in half, the American researchers are suggesting. Unlike currently available drugs which target reverse transcriptase, attacking the enzyme by limiting manganese transport from cells appears to be free of toxicities and would carry minimal risk of resistance emerging.
Lead researcher Jef Boeke commented on the findings: “These results really point to a never-before-proposed way to try and stop HIV in its tracks – that simply manipulating concentrations of a metal, manganese, can have a profound effect on reverse transcriptase. We expect the human equivalent of PMR1 could be a good target for developing new drugs against HIV.”
E C Bolton et al: Inhibition of reverse transcription in vivo by elevated manganese Ion concentration. Molecular Cell, Vol 9, 879-889, April 2002