By MITZI BAKER
Researchers at the School of Medicine have found in laboratory experiments a potentially novel way to prevent HIV infections in women.
They’ve discovered that bacteria that naturally live in the body can be genetically enhanced for potent antiviral activity. Modifications to this unique approach could lead to bacteria programmed to prevent infections from other sexually transmitted diseases or even respiratory viruses.
Enhancing bacteria that already colonize humans is a completely new strategy to combat viral invasion, said Peter P. Lee, MD, assistant professor of medicine. He and his colleagues have shown that a genetically engineered strain of lactobacillus – bacteria abundantly found in healthy vaginal mucosal linings – could significantly inhibit the ability of HIV to infect cells.
Their findings were published in Monday’s advance online edition of the Proceedings of the National Academy of Sciences.
Lee said that if the strategy works as well in humans as it does in cells, it may someday provide women with a safe, inexpensive and long-lasting way to protect themselves from HIV, the virus that causes AIDS. Lee’s work may offer a promising possibility to fortify the barrier that normally protects the vagina from foreign invaders.
"It struck me that viruses – certainly HIV, but almost all viruses – have to first get through the mucous membranes to get to the host," said Lee. "Essentially all mucous membranes of the body are colonized with normal, healthy bacteria. So why not try somehow to harness that and take advantage of these healthy bacteria to either block or inactivate viruses before they can get into a host?"
The predominant mode of HIV transmission worldwide is through heterosexual contact, with the risk of transfer from male to female far greater than the reverse. In the search for an agent to help prevent the spread of HIV, the methods have generally fallen into one of two camps: vaccines, which are difficult to construct against the constantly mutating HIV, or microbicides, which tend to be messy, irritating and short-lived.
An ideal preventive measure would allow a woman to discreetly protect herself against infection, an option not offered by condoms or microbicides that must be used immediately prior to exposure.
Lactobacillus already provides some protection against vaginal HIV transmission. Research has shown that women with little or no lactobacillus have a higher risk of contracting HIV and other sexually transmitted pathogens than those with high levels of the bacteria. For the study, Lee’s team gave the bacteria an extra boost by adding the gene for CD4, a protein that specifically latches on to HIV.
In the process of HIV infection, the virus first attaches to CD4 on the target cell. If HIV is caught up by CD4 on lactobacillus before it reaches a target cell, Lee reasoned, it could be a safe way of taking HIV out of commission.
"We have a two-pronged mechanism," said Lee, who explained that the trapped virus would additionally be exposed to antiviral compounds that lactobacillus normally produces, such as lactic acid and hydrogen peroxide.
Enhancing the already-protective lactobacillus gave HIV a double-whammy: a fully functioning natural barrier with a greater ability to block and inactivate viruses. "We’re making an organic preventative," said Lee.
When they tested their engineered bacteria in the laboratory, they found that it reduced the rate of HIV infection in susceptible cells by at least half. Their strategy is difficult to test in cell models, however, because the acid produced by lactobacillus itself kills cells.
Although there isn’t a good animal model for vaginal HIV transmission, preliminary studies using monkeys showed that the engineered bacteria grew well and proved to be safe. Lee said further research is needed to determine whether the therapy works as well in humans as it does in the laboratory experiments.
Lee said he envisions the research eventually leading to creation of a small vaginal suppository that a woman could use on a regular basis to provide ongoing protection. "It would be as discreet as can be," said Lee, adding that each dose could last a week or longer and could be inserted at any time, not just prior to exposure. He said he hopes to translate the technology to other viruses, such as the human papilloma virus, the herpes virus, or even the common cold or flu.
The researchers believe this is the first time such a method has been used to stymie a viral attack. Lee said genetically engineered bacteria have been used as vaccine delivery vehicles in the past but were designed to stimulate a strong immune response and were not comprised of naturally colonizing bacteria. "What we are doing is very different," said Lee. "We are trying to get the bacteria to directly bind and neutralize the pathogens themselves."
Collaborators include Gary Schoolnik, MD, professor of medicine, and Mark Holodniy, MD, associate professor of medicine, both in the division of infectious diseases. The study was funded by the National Institutes of Health and by the Contraceptive Research and Development Program of Eastern Virginia Medical School.
Stanford Report, September 10, 2003