There is increasing interest among HIV scientists in microbicides – chemicals that prevent HIV infection during vaginal or anal sex and can be incorporated into sexual lubricants and other products such as diaphragms.
The Tenth Retrovirus Conference saw a number of presentations of work in progress towards far more chemically-sophisticated and HIV-specific microbicides than have hitherto been developed.
To be an effective prevention tool in poor countries microbicides would have to be cheap, easily manufactured, universally available and culturally acceptable. Because of this the fast-track research has concentrated on very simple chemicals that disrupt or block HIV in crude ways.
These include surfactants (essentially, soaps) that dissolve the fatty HIV viral membrane. One example that has become notorious is nonoxynol-9, a compound already widely used as a spermicide. It certainly kills HIV, but because it damaged the rectal and vaginal lining was found to increase rather than decrease the likelihood of HIV infection.
Researchers have therefore moved on to gels that mimic protective mucus, and acids that counteract the alkalinity of sperm – HIV needs an alkaline environment. Even lemon juice has been suggested as a microbicide ingredient.
The problem with what Jeffrey Klausner, the director of the Bill and Melinda Gates Foundation, called ‘these large sticky molecules’ is that many of them have equally crude effects on the delicate vaginal membrane – not to say the thinner and even more delicate rectal one.
Microbicides also need to be not easily dispersed, should not be absorbed easily into the bloodstream where they could cause toxicity, and ideally need to be delivered in a way that enables them to penetrate quite far into the womb or (in the case of rectal use) up the colon. HIV-infected sperm, after all, is mobile and it has been found that the uterine and colonic cell walls are more vulnerable to HIV infection than tissues lower down. See here for more information.
The new ‘hi-tech’ microbicides in contrast incorporate already-developed or very new and experimental anti-HIV drugs. Some even have a ‘systemic’ effect, meaning that they block HIV infection some time after application by ‘proofing’ cells against HIV rather than by acting as a simple barrier.
One trial already incorporates a currently available HIV drug into a microbicide. Tenofovir is under investigation in gel form as a possible vaginal microbicide. Tenofovir gel has undergone phase I human safety study among US women and is about to start a phase II African trial.
Two candidates incorporate non-nucleoside HIV drugs (NNRTIs). One, dapivirine or TMC 120, was briefly under trial as an oral HIV drug by manufacturers Tibotec-Virco (now owned by Johnson and Johnson, the manufacturers of KY jelly – which may give it some advantage in development).
A microbicide containing dapivirine suspended in two different water-soluble gels, hydroxymethyl cellulose and carbopol 940, successfully prevented HIV infection in mice when it was vaginally administered 20 minutes before challenge with cells containing HIV genetically engineered to affect mice. The same investigators are now developing a cell line that mimics the rectal lining to see if dapivirine could work in anal sex too.
A second NNRTI, UC-781, was abandoned even earlier as an oral HIV drug due to poor bioavailability (a property which makes it ideal as a possible microbicide). A team from St George’s Hospital in south London has so far only tested it on cervical tissue in the test tube (and are preparing to do the same with rectal tissue). The most interesting observation was that the cells appeared to be proofed against HIV infection for as long as a week after application, suggesting that this compound may somehow be having a long-lasting systemic effect.
Other microbicide candidates include lectins. These are small proteins, found in plants, which bind closely to sugars. Those that bind specifically to the sugar mannose are under investigation as it is this sugar which predominantly coats the envelope protein of HIV (and incidentally makes it resistant to immune system attack by antibodies). Lectins are non-toxic, colourless, odourless and not absorbed into the bloodstream.
Two lectins, GNA (extracted from snowdrops) and HHA (from the garden plant amaryllis) were found to inhibit HIV at concentrations from 10 to 50 per cent of certain HIV drugs like tenofovir. They are active against HIV resistant to protease and reverse transcriptase inhibitors. Virus resistant to GNA has been developed but is not resistant to other HIV drugs, and – because it has to lose sugars to become resistant – may be more vulnerable to vaccines.
Another of the new generation of HIV drugs, the chemokine receptor inhibitors (CRIs), has also been used. These are drugs mimicking natural body chemicals that block the CCR5 molecules which sit on the surface of cells and act as essential co-receptors of the most commonly-transmitted variety of HIV.
Two newly-developed CCR5 CRIs, PSC-Rantes and UCB-Rantes, were found to block infection with HIV of Langerhans cells at concentrations comparable to oral IV drugs. These are cells that sit just under the surface layer of epithelial cells in the vaginal and rectal membranes and are thought to be among the first infected via abrasions or cuts in the membranes.
The highest-tech end of microbicide research is starting to look at what could be called ‘topical vaccines’ that actually incorporate anti-HIV antibodies. The broadly effective neutralising antibody b12 was incorporated into a hydroxymethyl cellulose gel and was used to protect half of a group of 25 Rhesus monkeys from infection. It turned a 92 per cent infection rate into a 25 per cent one.
b12 was only recently discovered in the blood of certain long-term nonprogressors. It is an elusive and expensive product that is currently also a hot candidate for a general vaccine, and is nether cheap nor stable enough to be used in widely available microbicides. But, as the investigators told me, they now have ‘proof of concept’ that a microbicide incorporating an immune defense can work. Other antibodies such as anti-ICAM have also been used as microbicide candidates. These will only become commercially viable if the antibodies can be made in bulk, possibly as ‘plantibodies’ produced by genetically-engineered plants.
One last idea is not to proof cells against HIV but to dampen down the very inflammation caused by compounds such as nonoxynol-9 – and by sexually transmitted infections- that facilitate HIV infection. One team of investigators found that women infected with cancer-causing variants of the human papilloma virus produced large amounts of the inflammatory cytokine (chemical signal) IL-8 from their cervical cells – this in turn makes them far more vulnerable to HIV. A small molecule called SB225002 is an IL-8 antagonist and could be used as an anti-inflammatory microbicide.
There will be many slips between this early research and the availability of a product that is cheap, potent and HIV-specific.
The last oral presentation on microbicides underlined this.
One very promising candidate has been BCD (2-hydrxypropyl-beta-cyclodextrin). This molecule has the property of removing cholesterol from both HIV the HIV envelope and CD4 cell membranes, and it is cholesterol-rich ‘rafts’ on cell membranes that appear to be the main points of entry for HIV. It is already known to be non-toxic and non-irritant as it is used as a carrier for topical itraconazole, and anti-thrush drug.
Experiments in monkeys showed that it reduced the likelihood of HV infection by a huge margin – there was at least 100-fold decrease in the likelihood of infection on cells in the test tube - and in more exacting studies on live animals a BCD microbicide cut the infection rate by SHIV (monkey HIV) from 80 per cent to 16.6 per cent.
However, surprisingly and very disappointingly, when the experiment was repeated on three monkeys that had already received the microbicide and viral challenge once before, all three became infected. It was as if a very fast-acting form of resistance or ‘memory’ to BCD had been set up in the vaginal cells. At the moment it is anyone’s guess how this has happened, and most explanations (a hidden inflammatory effect, fast-acting viral resistance) seem unlikely.
This result shows that the route to a simple and highly protective chemical that can be bought or supplied in every sexual lube may yet be a slow and tortuous one.