- Johns Hopkins scientists have found that simply increasing
manganese in cells can halt HIV's unusual ability to process its genetic
information backwards, providing a new way to target the process's key
driver, an enzyme called reverse transcriptase.
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- 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 is out of
whack, the enzyme doesn't work properly, they report.
-
- "Most reverse transcriptases we studied prefer to
bind magnesium. At the very least they were more active when magnesium
was bound to them," says Boeke. "But a little extra manganese
changes the activity of the enzyme."
-
- Normally, charged magnesium ions outnumber those of manganese
by the thousands inside cells. Having just three times more manganese than
normal can cut the activity of HIV's reverse transcriptase in half, the
scientists report, even though there's still much more magnesium.
-
- HIV's ability to adapt and overcome drugs means that
current treatments like AZT, which target reverse transcriptase directly,
generally stop working over time. Using a combination of drugs helps block
the virus on many fronts, but finding new drugs or a new class of drugs
is needed to help keep the virus at bay. The new work suggests that targeting
a cell's manganese transporter could be an effective way to stop HIV from
replicating, without targeting HIV's reverse transcriptase directly.
-
- "We've been working under the idea that studying
reverse transcriptase in yeast may help improve understanding of retroviruses
and lead to new ways to deal with HIV," says Boeke. "By studying
yeast genetics we made an important discovery about how HIV works and have
identified a target for a new class of anti-retroviral drug. It was completely
unexpected, but very satisfying."
-
- The yeast that were missing PMR1 appeared fine, suggesting
that targeting the manganese transporter in humans may be relatively safe,
the scientists suggest. It's not known whether targeting manganese levels
will have a therapeutic benefit, but the mantra of HIV treatment is to
reduce the number of copies of the virus.
-
- The studies were funded by the National Institutes of
Health. Albert Mildvan, M.D., professor of biological chemistry, is also
an author of the report.
-
-
- Editor's Note: The original news release can be found
at http://www.hopkinsmedicine.org/press/2002/APRIL/020425.htm
-
- Note: This story has been adapted from a news release
issued by Johns Hopkins Medical Institutions for journalists and other
members of the public. If you wish to quote from any part of this story,
please credit Johns Hopkins Medical Institutions as the original source.
You may also wish to include the following link in any citation: http://www.sciencedaily.com/releases/2002/04/020429072353.htm
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