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[Scott W]

NEWS RELEASE
The Center for North American Herpetology
Lawrence, Kansas
http://www.cnah.org
27 October 2005

Frog Secretions Block HIV Infections

Leigh MacMillan

A new weapon in the battle against HIV may come from an unusual source --
tropical frogs. Investigators at Vanderbilt University Medical Center have
discovered that compounds secreted by frog skin are potent blockers of HIV
infection.

The findings, reported this month in the Journal of Virology, could lead to
topical
treatments for preventing HIV transmission and reinforce the value of
preserving the Earth's biodiversity.

"We need to protect these species long enough for us to understand their
medicinal cabinet," says Louise A. Rollins-Smith, associate professor of
microbiology & immunology, who has been studying the antimicrobial defenses
of
frogs for about six years. Frogs, she explains, have specialized granular
glands in
the skin that produce and store packets of peptides, small protein-like
molecules. In response to skin injury or alarm, the frog secretes large
amounts
of these antimicrobial peptides onto the surface of the skin to combat
pathogens like bacteria, fungi and viruses.

Rollins-Smith happens to have the laboratory next door to Derya Unutmaz,
associate professor of microbiology and immunology. During a hallway chat
one
day, the two decided it would be interesting to investigate whether any frog
peptides have activity against human viruses, specifically HIV, the focus of
Unutmaz's group.

Postdoctoral fellow Scott E. VanCompernolle screened 15 antimicrobial
peptides
from a variety of frog species for their ability to block HIV infection of T
cells,
immune system cells targeted by HIV. He found several that inhibited HIV
infection without harming the T cells. The Australian Red-eyed Treefrog,
Litoria
chloris, had the highest levels of peptides that block HIV infection of all
species
that the researchers tested. The peptides appear to selectively kill the
virus,
perhaps by inserting themselves into the HIV outer membrane envelope and
creating "holes" that cause the virus particle to fall apart, Unutmaz said.

"We like to call these peptides WMDs - weapons of membrane destruction,"
Unutmaz quips. It is curious that the antimicrobial peptides do not harm the
T
cells at concentrations that are effective against the virus, he notes,
since
HIV's outer membrane is derived from, and therefore essentially identical
to, the
cellular membrane. The investigators have proposed that the peptides act
selectively on the virus in part because of its small size relative to
cells.

The ability of the peptides to destroy HIV was enticing, but to be really
effective
as antimicrobial agents, they need to prevent transmission of HIV from
dendritic
cells to T cells, Unutmaz said. Dendritic cells, he explains, are the
sentinels of
the immune system. They hang out in the mucus-generating surface tissues,
scanning for invading pathogens. "Their purpose in life is to capture the
enemy,
bring it to the lymph node - the command center - and present it to the
general,
the T cell, to activate a battle plan," Unutmaz says. "It's a very efficient
system
that has allowed us to survive many insults, pathogens, and viruses."

But HIV is a wily foe. When it is picked up at the mucosal surface by a
sentinel
dendritic cell, it somehow evades destruction. Instead, it hides inside the
cell,
waiting to invade the T cell with a Trojan Horse-like mechanism. The ability
of HIV
to remain hidden in the dendritic cell, avoiding destruction by circulating
antibodies and immune system cells, "may explain why after 20 years we don't
have a vaccine for this virus," Unutmaz says.

To test the effectiveness of the frog peptides in preventing HIV
transmission,
VanCompernolle first allowed cultured dendritic cells to capture active HIV.
He
then incubated the HIV-harboring dendritic cells with antimicrobial
peptides,
washed the peptides away, and added T cells. "Normally the dendritic cell
passes
the virus to the T cell, and we get very efficient infection of the T cell,"
Unutmaz
says. "But when we treated the dendritic cells with peptides, the virus was
gone,
completely gone. This was a great surprise."

The finding was puzzling, he explains, since the prevailing notion is that
HIV
captured by dendritic cells is hidden and protected. The investigators
currently
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