Since its discovery in 1981, AIDS has killed more than 25 million people worldwide. The human immunodeficiency virus, or HIV, causes AIDS, and the World Health Organization considers HIV infection a pandemic. About 0.6 percent of the global population lives with HIV, including an estimated 22.5 million people in sub-Saharan Africa.
But now, a powerful topical preventive for HIV could soon be a step closer to clinical trials, thanks to a newly discovered molecular compound that dissolves the virus on contact.
Researchers at Texas A&M University and the Scripps Research Institute have demonstrated the ability of the synthetic compound known as PD 404,182 to break apart the AIDS-causing virus before it can infect cells. The discovery was made by Zhilei Chen, assistant professor in the Artie McFerrin Department of Chemical Engineering at Texas A&M, and her team of researchers. Their findings appeared in the November 2011 online edition of Antimicrobial Agents and Chemotherapy 56(2): 672-681, a journal of the American Society for Microbiology.
"This is a virucidal small-molecule compound, meaning that it has the ability to kill a virus; in this case, that virus is HIV," Chen says. "Basically, it acts by breaking the virus open. We found that when HIV comes in contact with this compound, the virus breaks open and loses its genetic material. In a sense, the virus 'dissolves,' and its RNA becomes exposed. Since RNA is pretty unstable, once it is exposed it's gone very quickly, and the virus is rendered noninfectious."
The molecular compound discovered by Assistant Professor Zhilei Chen could help limit the spread of HIV when used in a preventive topical gel that dissolves the virus on contact.
The compound quickly rips open the virus before it can inject its genetic material into a human cell. What's more—and perhaps even more important—the compound, Chen explains, achieves this by acting on something other than the viral envelope protein. This means that the virus can't alter its proteins to bolster its resistance—something that's made HIV notoriously difficult to treat.
"We believe this compound is not working on the viral protein of the viruses but on something else common in all the viruses on which we tested it—some cellular material common in these viruses," Chen notes. "Because this compound is acting on a component that is not encoded by the virus, it will be difficult for the virus to evolve resistance against this compound."
Although not a cure for HIV, the compound shows significant potential for use as a preventive, specifically in the form of a topical gel that could be applied in the vaginal canal, Chen explains.
"We conducted a number of tests to demonstrate that this compound remains active in vaginal fluid and is not rendered ineffective," Chen says. "In the form of a vaginal gel, the compound would serve as a barrier, acting almost instantaneously to destroy the virus before it could infect a cell, thereby preventing HIV transmission from one person to another."
Surprisingly, Chen says she and her team did not set out to discover an HIV preventive. Instead, they were screening molecules for use in potential drug therapies targeting hepatitis C virus, which causes the dangerous and often fatal liver disease. Using a screening system that Chen developed, the team screened thousands of molecular compounds, in search of those that could block aspects of the HCV life cycle.
During the screenings, the team made an interesting discovery: Not only was PD 404,182 an HCV inhibitor, it also worked on lentiviruses (the group's negative control in its experimental procedures). Intrigued by that finding, Chen then tested PD 404,182 on HIV, also a lentivirus, and found the compound even more effective.
"This is a virucidal small-molecule compound, meaning that it has the ability to kill a virus; in this case, that virus is HIV."
"We believe PD 404,182 acts through a unique and important mechanism," Chen notes. "Most of the known virucidal compounds interact with the virus membrane, but our compound does not appear to interact with the virus membrane. Instead, it bypasses interaction with the membrane and still compromises the structural integrity of the virus."
The compound's ability to avoid interaction with the virus membrane is important because human cells have similar membranes, Chen notes. If the compound were to disrupt the structure of the virus membrane, it could also disrupt and ultimately kill human cells. PD 404,182 doesn't interact with these membranes and is therefore a more attractive option for clinical treatment, Chen says.
As with any potential pharmaceutical, several key steps are still needed before it winds up on drugstore shelves. In addition to several rounds of animal studies to ensure that the compound is safe for humans, further collaborations with chemists are needed to continue to improve the efficiency of the compound. Chen says she also plans to further explore precisely how PD 404,182 breaks apart HIV.
This work is a collaboration between Chen's team, consisting of graduate students Ana Maria Chamoun and Rudo Simeon; postdoctoral associate Karuppiah Chockalingam; and Professor Philippe Gallay's team at the Scripps Research Institute.