By measuring DNA produced by a related reverse transcriptase in yeast, the Hopkins team discovered that higher than normal levels of manganese, caused by a defective gene, dramatically lowered the enzyme's activity. The scientists then proved that HIV's reverse transcriptase responds to manganese in the same way.
Hopkins graduate student Eric Bolton determined that the defective gene is PMR1, whose protein carries both manganese and calcium out of cells. Using special yeast developed by others at Hopkins, he discovered that manganese stops reverse transcriptase, the team reports in the April 26 issue of Molecular Cell.
"These results really 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 on reverse transcriptase," says Jef Boeke, Ph.D., professor of molecular biology and genetics at the school's Institute for Basic Biomedical Sciences. "We expect the human equivalent of PMR1 could be a good target for developing new drugs against HIV."
Retroviruses like HIV use reverse transcriptase to make copies of their DNA from RNA, the opposite of how genetic information is usually processed in cells. Each retrovirus has a distinct version of the enzyme, identical in function but different in form and sequence, says Boeke, also a professor of oncology.
The scientists found that each reverse transcriptase they studied has at least two places where manganese and the similar metal magnesium can "dock." Having these spots filled with the right metal is crucial for the enzyme's activity -- its ability to read a particular set of RNA, the scientists learned. When the metals' balance
Contact: Joanna Downer
Johns Hopkins Medical Institutions