A new weapon in the battle against HIV may come from an unusual source -- a small tropical frog.
Investigators at Vanderbilt University Medical Center reported this month in the Journal of Virology that compounds secreted by frog skin are potent blockers of HIV infection.
The findings could lead to topical treatments for preventing HIV transmission, and they reinforce the value of preserving the Earth's biodiversity.
"We need to protect these species long enough for us to understand their medicinal cabinet," said Louise A. Rollins-Smith, Ph.D., associate professor of Microbiology & Immunology, who has been studying the antimicrobial defenses of frogs for about six years. Frogs, she explained, 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, M.D., associate professor of Microbiology & 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, Ph.D., 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 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 said. It is curious that the antimicrobial peptides do not harm the T cells at concentrations that are effective against the virus, he noted, 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 explained, are the sentinels of the immune system. They hang out in the mucosal 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 said. "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 said.
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 said. "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 added, since the prevailing notion is that HIV captured by dendritic cells is hidden and protected. The investigators currently are using imaging technologies to test the hypothesis that HIV is actually cycling to the dendritic cell surface.