Contents
- Cover Story
Exploring the Potential of HIV Microbicides
Cover Story
Exploring the Potential of HIV Microbicides
Women and AIDS
The number of women with HIV infection and AIDS has increased steadily. By the end of 2005, of the 38.6 million people living with HIV, almost half (17.3 million) were women, according to the World Health Organization. The vast majority (76%) of HIV-infected women live in sub-Saharan Africa. In the United States, the proportion of adult HIV casesa mong women has more than tripled in the past two decades—from 8% in 1985 to 25% today, according to United Nations and U.S. Centers for Disease Control and Prevention statistics. HIV infection disproportionately affects the nation’s African-American and Hispanic women. Together, these two ethnic groups represent less than 25% of all U.S. women, yet they account for 79% of women with HIV nationally.
Miller and his colleagues recently found that new SIV infections in female macaques remain limited for about four days to a relatively small number of cells, primarily in the vagina and cervix. “There’s something of a delay between the time that the virus comes in contact with the genital tract and the time that full-fledged systemic replication of the virus occurs,” says Miller. This finding suggests that microbicides might do more than just block sexual transmission of HIV. If a woman has already become infected through sexual contact, a microbicide, if administered soon enough, might prevent or limit a wider systemic HIV infection. “It gives people hope and a rational basis to keep exploring interventions that are aimed at an early timepoint,” he says.
At the Tulane NPRC, another NCRR-funded primate center, Ronald Veazey and his colleagues are testing a promising new type of microbicide called a fusion inhibitor. These agents inhibit infection in a specific and targeted way by preventing the binding, or fusion, between glycoprotein molecules on the outer coat of HIV particles and the receptors for those glycoproteins on the surface of immune cells.
Veazey studies fusion inhibitors that target a type of cellular receptor called CCR5. As one of the main receptors that HIV uses to infect cells, CCR5 appears to play a major role in HIV transmission across mucosal surfaces, like those in the vagina. When these fusion inhibitors bind to a cell’s CCR5 receptors, they block viral access to the receptors and in some cases also trigger cellular changes that reduce the number of receptors on the cell’s surface. These mechanisms greatly limit viral entry points into the cell.
Veazey and his colleagues have found that both vaginal and oral administration of CCR5-based fusion inhibitors protects macaques against infection. “We’ve shown tremendous proof of concepts in blocking this receptor,” says Veazey. “Blocking CCR5 seems to be all that is necessary to prevent transmission of the AIDS virus, at least in the monkey model.”
In one study, the researchers administered three experimental microbicide gels, alone and in combination, to female macaques and found that all three were protective against vaginal infection with simian HIV. In addition, significant protection was achieved when two of the agents—known as Compound 167 and BMS-378806—were administered in combination. The combination gel was protective, even when applied up to six hours before viral exposure. In a separate study, Veazey and colleagues found that orally administered formulations of Compound 167 can prevent vaginal infections of simian HIV in macaques.
Scientists are now working to develop more cost-effective molecular preparations of fusion inhibitors. “Clearly, the CCR5 point of attack is extremely effective. Our major obstacle now is to develop a fusion inhibitor that can be produced economically,” says Veazey. Clinical trials of the fusion inhibitor gels are now being planned.
Another novel approach to microbicide development is being pursued in preclinical studies at the NCRR-funded RCMI at Meharry Medical College in Nashville. James Hildreth, director of Meharry’s Center for AIDS Health Disparities Research, is investigating an agent called beta-cyclodextrin. Cyclodextrins are simple polymer sugars that are already widely used in a variety of products, including mouthwash, topical creams, food flavorings, and some intravenous medications.
“Cyclodextrin is easy to synthesize, very inexpensive to produce, and if it works it will cost about 7 cents per application,” says Hildreth. “For developing countries, where the annual income is often only a few hundred dollars per year, we have to produce something that is very inexpensive.”
