Cervical findings may alter microbicide development

Critical HIV receptor found primarily in cervix

As clinical trials begin on a new vaginal microbicide designed to block the first step of HIV infection, Harvard Medical School researchers have found that the surface of the cervix may be the exact location where infection takes place.

Preliminary findings from cervical scrapings taken from HIV-negative women undergoing hysterectomies at Brigham and Women’s Hospital in Boston have found high concentrations of a chemokine receptor known as CCR-5. Last year, several research labs identified CCR-5 as an HIV co-receptor that must be present in order for HIV to enter and infect CD4 cells. By testing cervical tissues, Harvard researchers have found that CCR-5 is predominantly found in the cervical area, says lead researcher Deborah Anderson, PhD, associate professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School in Boston.

"People have long debated if it is the cervix or the vaginal wall that is the most important for HIV infection," she tells AIDS Alert. "What we are finding is the highest concentration [of CCR-5] in the cervix. I can’t say we aren’t detecting anything in the vaginal wall, but the cervix seems to be the hot spot."

Because the study results are not yet published, Anderson is reluctant to share details of the research. However, she says the findings could have important implications for microbicide research.

"I think it’s good news for microbicides," he says. "It is easier to protect the cervix than the entire vaginal surface, especially if they are used with a small cervical cap or diaphragm."

Pam Stratton, MD, a researcher in the contractive branch of the National Institute for Child Health and Human Development in Bethesda, MD, and an expert in microbicide research, agreed that the finding could influence microbicide research.

"Having this connection could justify looking at combinations of barriers and microbicides that cover the cervix," she says.

CCR-5 provides entry into CD4 cells

How HIV binds to CD4 cells was a mystery until last summer when several researchers began focusing on chemokines, a protein that helps orchestrate the immune response. One of those researchers, Robert Doms, PhD, associate professor of pathology at the University of Pennsylvania School of Medicine, found that HIV uses the chemokine receptor CCR-5 to gain entry into CD4 cells. In patients who lacked the CCR-5 receptor, HIV infection did not take place. An estimated 1% of Caucasians don’t have CCR-5.

"Women as well as men who lack CCR-5 are very highly resistant to virus infection," he says. "They are not immune to the virus but highly resistant, so that basically proves how important CCR-5 is for virus transmission."

Harvard researchers are initiating a study that will monitor CCR-5 receptor levels in women who have sexually transmitted diseases or other vaginal infections that put them at high risk for HIV infection. The women in the initial study who had come to the hospital were at low risk for HIV infection. "We would predict that a vaginal or cervical infection would increase the level of CCR-5 expression in the genital tract because CCR-5 is expressed primarily on activated macrophages and T-cells," Anderson explains.

Without more details about the findings, Doms says he cannot comment on the Harvard study. However, he notes that other researchers are working hard to find where in the body CCR-5 is expressed. One important question that needs to be answered is whether the virus can bind directly to CCR-5 in the absence of CD4 cells, Doms adds.

The developers of a microbicide called Pro2000 are confident that HIV infection cannot take place without the presence of CD4 cells and have developed a compound that blocks the virus from entering a woman’s T cells.

"We are confident that CD4, being an immutable, human protein, is constant across all cells and that by blocking the virus’ entry, it [Pro2000] should be sufficient to prevent infection," says Stanley Erck, president of Procept, the Cambridge, MA, biotechnology company that developed the microbicide.

Developed from a naphthalene sulfonate polymer, Pro2000 is relatively simple to produce, remains stable for more than a year, is tasteless, and is compatible with latex condoms. The topical gel has been shown in labs to suppress infection of both T cells and macro phages by a wide range of HIV-1 isolates, including primary clinical isolates and those of African origin.

Although the product is 10 times more potent than nonoxynol-9, it was less irritating than N-9 in rabbit studies, Erck says.

Because Pro2000 blocks the infection mechanism — unlike N-9, which attacks the virus — there is less concern about effectiveness against different strains of the virus resulting from inadequate drug treatment, he adds.

Compound may inhibit sperm

Studies are under way to determine whether the compound acts as a contraceptive or not. Although it is not a spermicide, it may inhibit the ability of sperm to function, Erck explains. Health officials have argued for the need to have two types of microbicides for different cultures — one that kills virus but doesn’t act as a contraceptive, and another that kills both virus and sperm.

Phase I clinical safety trials of Pro2000 are under way in Antwerp, Belgium, and London through a $1 million grant from the British Medical Research Council. Based on these studies, Phase 2 studies are planned for later next year.

One issue is how many patients would be needed for Phase 2 or Phase 3 studies, says Erck. Trial size likely will depend on the results of the long-awaited N-9 study of women in Cameroon (See related story in AIDS Alert, January 1997, pp. 4-6.) The results of the trial, which concluded in December, should be made public by April, says Nash Herndon, spokesman for Family Health International in Research Triangle Park, NC.