www.latimes.com/features/health/la-sci-microbicide5-2009mar05,0,11717

With AIDS vaccine efforts at an impasse, microbicides -- virus-blocking gels inserted into the vagina before sexual intercourse -- have risen from their own string of setbacks to once again offer hope of preventing HIV infections, at least in women.

Microbicides blocked the primate form of the virus in monkeys in studies reported online Wednesday in the journal Nature and last month at an AIDS meeting. A third microbicide tested in 3,100 women showed potential for protection in findings presented at the meeting in Montreal.

Identifying a microbicide that works even partially could have a huge effect. Almost half of the more than 33 million people living with HIV worldwide are women; in sub-Saharan Africa, the figure is 60%.

"It would empower women to protect themselves in a sexual situation in which they may not have complete control," said Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases.

Abstinence and condoms have been the only proven ways to prevent or reduce the spread of HIV among adults. Circumcision lowers the risk for men, and already-existing AIDS drugs are used prophylactically to reduce mother-to-child transmission during birth or breast-feeding.

In many parts of the world, it is difficult or impossible for women to refuse sex or persuade a partner to use a condom. An effective microbicide would be something that women could initiate on their own.

Microbicides might also prevent infection during anal intercourse, although most studies have focused on vaginal transmission.

That scientists would be so encouraged by two animal studies and a minor success in a human trial is a sign, in part, of how stymied they have been in two decades of trying to find a microbicide or a vaccine to stem the spread of HIV.

"There's no vaccine on the immediate horizon," said Dr. Lynn Paxton of the U.S. Centers for Disease Control and Prevention. "After a number of microbicide trials failed to show any effect or in some cases showed a negative effect, this is good news."

Until now, all microbicides tested in human trials have failed -- two spectacularly in that they increased the risk of infection.

In 2000, human trials of nonoxynol-9, a spermicide gel already used for birth control, were halted because the gel was found to irritate the vaginal lining, making it easier for the virus to gain entry. In 2007, human trials of a cellulose sulfate gel were halted after it was also found to increase vulnerability to the virus.

Experimental vaccines have also proved disappointing. For 25 years, U.S. health officials have vowed to get a vaccine to the market, saying it was the best hope for containing the AIDS pandemic.

But two years ago, a much-anticipated human trial of a Merck & Co. vaccine was halted not only because the vaccine wasn't working, but out of fear that it also might have increased the risk of infection.

And last year, U.S. health officials called off plans for a large human trial ofwhat had been considered a promising vaccine, and urged scientists to go back to basic research on the immune system and animal tests.

Antiretroviral drugs have been the one concrete success in the AIDS battle, almost overnight commuting what had been a certain death sentence into, for most people, a manageable chronic disease.

But the drugs have limitations. They are expensive. They suppress HIV but don't cure it, so they must be taken for life. Although advancements have eliminated many side effects, no one knows what the cumulative effects of the drugs will be or whether they will eventually stop working. And for some people, the drugs simply don't work.

What is promising about the recent experiments, researchers say, is that each of these so-called next-generation microbicides uses a more targeted strategy than earlier efforts. The early microbicides attempted to block the virus from attaching to the cell lining of the vagina. The new microbicides target the virus itself.

The human trial reported last month at the Conference on Retroviruses and Opportunistic Infections involved a vaginal gel called PRO 2005/5 that acts by binding to HIV and hindering its entrance into human cells. The gel reduced infections by 30% when tested in women in six sites in Africa and one in the United States -- shy of the 33% protection that would have been considered statistically significant.

Despite the statistical shortfall, this was the first human clinical study to provide a glimmer of hope. A larger study by British and African researchers on 9,100 women is in progress; interim results are expected this year.

The monkey experiment presented at the Montreal conference used already-existing antiretroviral drugs in a vaginal gel. The 12 monkeys exposed to the virus after receiving the gel were protected from the monkey form of HIV; 10 of the 11 monkeys that did not receive the gel became infected.

The study published Wednesday in Nature used a third approach that focuses on the body's immune response.

After exposure to HIV, the immune system rushes infection-fighting T cells to the site. But these are the very cells that HIV hijacks and uses to spread infection throughout the body.

Dr. Ashley Haase, head of the microbiology department at the University of Minnesota Medical School, and colleague Patrick M. Schlievert, a microbiologist, found that a naturally occurring compound called glycerol monolaurate dampens the immune response to the primate version of HIV, depriving the virus of cells to infect.

Five of five monkeys given a vaginal gel containing the compound showed no signs of infection two weeks after being exposed to the virus; four of five monkeys not given the vaginal gel were teeming with viruses.

"It is a relatively preliminary study but worth sharing because it establishes a novel approach," Haase said.

But one of the five monkeys that had initially tested negative for HIV was tested again months after the experiment ended and found to be infected, a sign that an undetectable level of virus had been transmitted and later established itself.

The scientists said that more animal trials were needed to test whether the microbicide should be given over a longer time or at a higher dose to prevent breakthrough infections.

A mathematical model suggested that even if a microbicide were only 60% effective and used just 20% of the time, it could prevent 2.3 million new infections over three years, they said.

mary.engel@latimes.com