What's in the Pipeline?
Do women want a vaginal HIV microbicide? The answer is a resounding yes, judging by a recent international survey of women in 12 developing countries-the first of its kind-commissioned by the European Union's HIV/AIDS program. The report was presented at the 12th World AIDS Conference in Geneva and found that up to 80 percent of women surveyed in some countries, many being at high risk for HIV, say they are very keen to lay their hands on an effective microbicide. Others, including gay and bisexual men, are interested in a rectal microbicide.

According to the Maryland-based Alliance for Microbicide Development, a private advocacy group, there are at least 47 biopharmaceutical firms and academic and independent research centers in the United States trying to develop microbicides. Here are the leading candidates:

• pH-lowering compounds. A number of products are being tested in early human studies that appear to lower vaginal pH and protect the vagina from HIV and STDs (see main story). Clinical trials are under way testing a lactobacillus suppository, as well as BufferGel, developed by ReProtect, a small biotech firm in Baltimore. BufferGel is designed to keep the vaginal pH low in the presence of semen. In a test tube, BufferGel also kills chlamydia, syphilis, gonorrhea, and various HIV strains.

• "Invisible Condom" A waterproof liquid that hardens in the vagina to form a barrier against viruses and bacteria looks promising. Early tests by Canadian researchers at Laval University show the nontoxic polymer-based gel reduced transmission of HIV and the virus that causes genital herpes. Human clinical trials are being planned here and in Canada.

• Immunoglobulins (antibodies) are germ killers that are produced by plasma cells that reside in tissue underneath the vaginal epithelium. They are carried through epithelial cells out to the genital tract secretions, where they bind to HIV and neutralize the virus. Can we give women antibodies that protect them? Studies are under way to find out.

• Defensins (antimicrobial peptides) are very small molecules that non-specifically kill a wide range of microorganisms (fungi, bacteria, and viruses) by punching holes in their outer membranes. Unfortunately, they're costly to manufacture. A top contender, Human Defensin 5, acts like a natural disinfectant. Human beta defensin 1 (HBD-1) is a naturally occurring antibiotic that seems to be deficient in women who get chronic vaginal infections; replacing HPD-1 deficiencies might help prevent STD transmission.

• Cytokines (inflammatory proteins) are molecules that act as chemical messengers between cells. When infectious organisms enter the vagina, these cytokines swing into action. Some have pro-inflammatory effects that might enhance HIV or STD infections; others might help decrease transmission.

• Protegrins are a type of naturally occurring, fast-acting, broad-spectrum germ killer produced in the white blood cells of pigs. Test-tube studies show protegrins can kill HIV and several bacterial STDs. Phase I safety studies show protegrins appear safe for topical use, but their safety for vaginal use hasn't been determined. Unfortunately, protegrins appear to inactivate lactobacilli, based on preliminary data by Robert Lehrer of the UCLA Medical School.

• Monoclonal antibodies are "inhibitors of viral entry" under study that will ideally coat the vagina and prevent HIV-infected cells from attaching to the vaginal wall. The New York-based Population Council recently completed Phase I studies of two promising sulfated polysaccharide compounds (PC-213 and PC-503). Researchers at St. Mary's Hospital in England also completed a safety study of Dextrin Sulfate, another potential inhibitor of viral entry. Another candidate, PRO 2000, is a clear sticky gel developed by Procept, Inc. in Cambridge, Massachusetts, that was well tolerated by healthy women in two recent safety trials. A larger, multicentered safety study of PRO 2000 is scheduled to begin soon.

-AF