Special Edition, Spring 2002

STI Prevention
Toward the Development of a Microbicide

The spread of AIDS and other sexually transmitted diseases (STDs) has created an urgent need for products that women can use to protect themselves from these infections. Developing one such product—called a microbicide—is the goal of research in the laboratory of David Phillips, a virologist at the Population Council’s Center for Biomedical Research. Phillips’s scientific team has been working since 1989 to understand the basic biology of HIV infection and to test compounds that could prevent transmission of HIV and other STD pathogens. Research on both fronts has yielded significant results in recent years, increasing the prospects that women will one day have access to a vaginally applied product that guards against STD infection—either in contraceptive or noncontraceptive form.

Devising a product that is useful to women in developing countries is a priority for Council researchers. To this end, Phillips collaborates with Council colleague Christopher Elias in the Programs Division to engage a group of women’s health advocates in the process of microbicide development. Feedback from this group is helping to steer development toward products that meet the needs and accommodate the preferences of women in places where these products are most needed.

From basic to applied research
“Microbicide” is actually a misnomer for the most promising compounds under investigation in Phillips’s lab. These substances do not kill microbes; rather, they prevent them from adhering to the epithelial cells that form the outer layer of the reproductive tract.

The decision to test compounds that work in this way was informed by basic research findings in the lab. Prior to this research, scientists presumed that HIV infects the body by entering the bloodstream as “free virus” (independent of a host cell). “Strategies to prevent infection, such as proposed AIDS vaccines, have been based on this assumption,” Phillips says.

Most infectious microorganisms enter the body through the intact epithelium of the respiratory, digestive, urinary, and reproductive tracts. Scientists assumed that HIV could not enter this way because epithelial cells lack receptors for the virus. Instead, they hypothesized, HIV must infect the reproductive tract by entering through lesions in the epithelium.

Phillips’s research team challenged this assumption by showing that HIV can infect intact epithelial cells in vitro (in the test tube). HIV appears to enter the epithelium Trojan-Horse-style—hidden within cells of the immune system. Carried in semen or vaginal secretions, the HIV-infected cells adhere to the reproductive tract epithelium of the sexual partner, then secrete virus onto it.

This finding suggests that transmission of HIV to women through sexual intercourse might be thwarted by coating the female reproductive tract with a substance that inhibits HIV-infected cells from adhering to the epithelium. To be a viable candidate for product development, the substance would not only have to be effective, but also safe, inexpensive, chemically stable, nonirritating, and not absorbed by the body (to prevent side effects). Ideally, it would block infection not only by HIV, but by other STD pathogens as well.

Phillips’s team recently identified a group of compounds that appear to fit these requirements: the sulfated polysaccharides—substances found in every plant and animal. Some of them block infection by chlamydia as well as HIV in vitro. A formulation containing one of these compounds was shown in a Phase 1 clinical trial to be nonirritating to the vagina.

Promising as these scientific advances are, “a long and costly road exists between a concept and a product,” Phillips observes. More research questions must be answered, and obstacles to product testing and manufacture overcome, before microbicides take their place next to spermicides on clinic and pharmacy shelves.” Originally published in Population Briefs 2(3), Summer 1996.

Sources
Pearce-Pratt, R. and D.M. Phillips. 1996. “Sulfated polysaccharides inhibit lymphocyte-to-epithelial transmission of HIV,” Biology of Reproduction 54: 173–182.

Phillips, David M. 1995. “Intravaginal formulations to prevent HIV infection,” in J. Fantini and J. Sabatier (eds.), Perspectives in Drug Discovery and Design, vol. 5. Leiden, Netherlands: ESCO, pp. 213–223.

Phillips, David M., Vanaja R. Zacharopoulos, Xin Tan, and Rachael Pearce-Pratt. 1994. “Mechanisms of sexual transmission of HIV: Does HIV infect intact epithelia?” Trends in Microbiology 2(11): 454–458.  

Outside funding
National Institutes of Health, the Rockefeller Foundation, Swedish International Development Cooperation Agency, and United States Agency for International Development.

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