United Press International - April 25, 2002
Steve Mitchell, UPI Medical Correspondent

Human immunodeficiency virus depends on an enzyme called reverse transcriptase to replicate, and a team of researchers at Johns Hopkins University in Baltimore found higher than normal levels of manganese lower the activity of a similar enzyme used by a virus-like component of yeast.

Further research determined increasing manganese also lowers the activity of HIV's reverse transcriptase, which could block replication of the virus and help prevent it from causing acquired immune deficiency syndrome.

If drugs could be developed that increase manganese levels, it would be a novel approach to treating HIV, Jef Boeke, professor of molecular biology and genetics at Johns Hopkins University and principal investigator in the study, told United Press International in a phone interview.

Boeke said his team currently is looking for drugs that do just that. The higher levels of manganese in yeast were caused by a defective gene called PRM1, which produces a protein that shuttles manganese out of cells. The Hopkins scientists, in research published in the April 26 issue of Molecular Cell, said they expect the human equivalent of PRM1 will be a good target for drugs designed to treat HIV infection.

Boeke cautioned, however, it is not yet known whether raising manganese levels in humans will have any therapeutic effect.

One of the first treatments for HIV infection, the antiretroviral zidovudine -- AZT -- targeted reverse transcriptase. The virus is notorious for developing resistance to drugs, however, so new treatments are needed to keep it in check.

Drugs that target PRM1 and increase manganese levels may help prevent the development of resistance, Boeke said.

HIV may still develop resistance but "a new class of agents would still be really useful because what has really been successful is combining drugs," he said.

Carl Dieffenbach, associate director for basic sciences in the AIDS program at the National Institutes of Health's Institute of Allergy and Infectious Diseases in Bethesda, Md., said the research was done in a test tube and adjusting metal ion concentrations in the body could have completely different results.

Dieffenbach told UPI the study will spur a flurry of research to further understand whether the PRM1 gene is a viable target to develop drugs around.

"The first step will be to do a study in mice," Dieffenbach said. At the same time, researchers also can look at people infected with HIV and see if they can detect any with a defect in the PRM1 gene. If they do find a defect, they can determine if they are protected from HIV infection or have a slower progression of disease.

"Within two to three years, we'll know if this is a viable target," he said.
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