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Pulling the Wool Over HIV

By Kurt Kleiner

On a research farm in Baltimore County, Md., a couple of alpacas might one day help protect women from HIV infection.

Richard Markham, MD, a professor of Molecular Microbiology and Immunology, is using the alpacas to develop an antibody that interferes with HIV's ability to infect women through intercourse. Eventually, women might be able to apply a product vaginally that would protect them for weeks or longer from infection.

The search for a protective microbicide has been long and frustrating. Researchers hoped that microbicides applied as vaginal creams or gels might interfere with the human immunodeficiency virus. But clinical trials showed that two products actually enhanced infection rates, and a third called Carraguard recently was shown to provide no protection.

And even if the cream- or gel-based microbicides did work, there's another problem: Women don't like using them. On average, women in the Carraguard study used the cream only 44 percent of the time.

"For some of these products, it's like having sex through toothpaste," Markham says. "First of all you have to stop and apply this stuff in the immediate precoital period. It detracts from the sexual experience."

So Markham and colleagues are trying to develop an antibody that both interferes with HIV's ability to infect and that can be produced by bacteria naturally found in the vaginal tract. And they are using the alpacas to create the antibody in the first place. (Antibodies are proteins produced by the immune system to defend the body against bacteria, viruses and other threats.)

HIV mutates quickly, and it has been hard to develop a vaccine against it. But as viruses replicate they often incorporate host proteins. HIV picks up a human protein called LFA-1, and it is this human protein on the surface of the virus that Markham is trying to target.

Normally, the body produces antibodies that attach themselves to foreign pathogens. An antibody that targeted LFA-1 would attach itself to the protein and interfere with the virus's ability to penetrate the human cell and replicate.

So Markham and colleagues decided to engineer lactobacilli, which naturally occur in the vaginal tract, to produce an antibody to the LFA-1 protein. These are benign bacteria, which are the same ones found in yogurt. Since antibodies themselves are big, complicated and fragile, they created smaller antibody fragments to target the protein and block HIV transmission. But they had only partial success.

So they decided to try something called a single-domain antibody, an even smaller antibody produced by camelids, such as camels, llamas and alpacas. Markham has produced a single-domain antibody specific to LFA-1, and is working with Swedish colleagues to engineer a strain of lactobacillus that will express the antibody.

He originally expected to work with llamas, but discovered that they are extremely aggressive—in fact, they are used to guard packs of sheep from wolves. Then he discovered that the smaller and more mild-mannered alpacas would work just as well.

Ultimately, Markham wants to create a product, such as a suppository, containing the antibody-producing lactobacilli that a woman can apply, allowing the bacteria to colonize her vagina. Ideally, the bacteria would stay in place for months, producing the antibody and providing protection from HIV infection. Unlike traditional microbicides, this protection would be completely transparent to the users.

Markham still has to engineer the bacteria and show that the treatment is safe and effective in humans. But he thinks it can be done. "I'm optimistic we can proceed pretty rapidly," he says.