ONCE a Cinderella subject, creams that block HIV infection during sex have now become a major focus of AIDS research. But at the Microbicides 2004 conference in London last week, it was clear that many hurdles will have to be overcome before any become available.
Prevention campaigns focus on condoms, but not everyone is happy to use them and many women, especially in developing countries, cannot insist that their partners wear condoms. Hence the interest in microbicides, or 鈥渃hemical condoms鈥�, in the form of a cream or pessary that women could apply before sex to destroy the virus or stop it getting into cells. People would be advised to use a cream with a condom, but the idea is that a cream by itself would prevent or greatly reduce the chances of HIV infection.
One of the hurdles researchers face, though, is that we still do not understand exactly how HIV is transmitted through semen and genital secretions. It is not known whether virus-infected cells or free viruses are chiefly to blame. Nor is it clear how many different types of immune cell are vulnerable to infection.
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Because multiple pathways are involved, several chemicals might have to be combined to create an effective microbicide. 鈥淵ou may not get complete protection if you use an agent that blocks only one pathway,鈥� John Moore of Cornell University told the conference.
Microbicides will also have to be provided in forms acceptable to different cultures. In some parts of Africa there is a tradition of 鈥渄ry sex鈥�, in which women use herbal medicines or absorbent materials to reduce moisture in their vagina in the belief that lubrication is a sign of promiscuity and diminishes male enjoyment. In a survey in Zambia nearly half of women reported this practice, suggesting they would be reluctant to use microbicide creams.
But there are reasons for optimism. One promising strategy involves RNA interference (RNAi), a natural system used by cells to temporarily 鈥渢urn off鈥� certain genes. This is already creating much excitement as a new way of tackling diseases such as cancer and viral infections (麻豆传媒, 14 September 2002, p 28).
Judy Lieberman of Harvard Medical School in Boston has now developed an RNAi therapy against the human CCR5 gene, which codes for a membrane protein that HIV binds to when it infects cells. Turn off the CCR5 gene and the protein soon disappears from the surface of cells, meaning HIV cannot get in.
Tests on immune cells show that a single dose of the RNAi agent blocks viral replication for several weeks. If it works as well in people, it might be possible to develop a microbicide that only has to be applied monthly. 鈥淵ou would not need to use it just before sex,鈥� Lieberman says.
This is just one of around 50 compounds that are being tested in cell cultures or animals. Other approaches being investigated include creams containing the antiretroviral drugs used to keep AIDS at bay, a natural immune protein called gp340 that stops HIV binding to cells, and using the female hormone oestrogen to thicken the vaginal lining.
But for researchers in the field, the greatest cause for optimism is that this year six products are due to enter large-scale clinical trials lasting three years. Four consist of charged polymers that prevent HIV binding to cells. The other two inactivate the virus 鈥� one is a detergent and the other is a buffer designed to keep the vagina acidic even when alkaline semen arrives.
These trials are vital to ensure microbicides do not damage the vaginal lining, which is not only undesirable in itself but also increases the risk of HIV infection. 鈥淚n no other field are safety and efficacy so intimately linked,鈥� says Janet Darbyshire, head of the clinical trials unit of the UK鈥檚 Medical Research Council.
She points out that the spermicide nonoxynol-9 was once touted as a potential microbicide. However, trials showed it damaged the vaginal lining and actually increased the likelihood of infection.
