HIV Prevention Using Microbicides

HIV prevention is a “hot” research area. A lot of time and money is being spent to try to prevent HIV spread. There are several avenues of research for HIV prevention, but 2 of the most popular are vaccines and microbicides. A vaccine (with low production and distribution cost) for HIV would be ideal, particularly if it offers long term protection with no need for a booster. However, it has been very difficult to develop an efficacious vaccine. HIV mutates rapidly, which means that immunity to one version of HIV might not protect you from a different version of the virus (sort of like getting the flu even though you’ve had the flu vaccine). Due to the lack of success with vaccines, several research groups (mine included) are pursuing alternative prevention strategies, such as microbicides.

Now, you may wonder why we are focussing on coming up with new ways to prevent HIV infection when condoms can efficiently prevent HIV infection. There are lots of reasons why people don’t use condoms. In the developing world, where HIV burden is the highest, many women are not able to insist on condom use, due to cultural or societal norms. These women represent more than 50% of the new HIV infections that occur each year. Since the standard prevention options are not feasible for them, an alternative needs to be designed. This is why we are focusing on microbicides – ideally, women could use them prior to intercourse and their partner doesn’t need to know.

Microbicides are drug products that are can be topically applied to the vaginal or rectal tract to prevent infection with HIV. Many microbicides have been under development for HIV, but none have been brought to market yet. Several are undergoing clinical trials, and several have already failed in clinical trials. Tenofovir is one microbicide that I have been hearing a lot about recently. Tenofovir is an anti-retroviral that has been formulated into a microbicide gel. Tenofovir was successful in its’ first clinical trial, showing protection rates of 39%. However, the second trial was recently stopped because no difference was observed between the drug group and the placebo.

An emerging area of microbicide development is the use of engineered bacteria. Several research groups have focussed on Lactobacillus which is a normal component of the vaginal microflora. They hope that by engineering Lactobacillus to express or secrete an anti-HIV protein they can, with one application, provide long-term protection from HIV infection. Ideally, there would be no need to reapply the Lactobacillus microbicide, because the bacteria would be able to live in the vaginal tract, and should (in theory) continually express the protein. However, what do you do if some sort of side effect occurs? How do you kill the engineered bacteria without destroying the natural vaginal microflora? How do you know the bacteria is still expressing the protein?

There are a lot of issues that can arise from the use of Lactobacillus as a microbicide. My research is investigating an alternative engineered bacteria based microbicide system, using a bacteria called Caulobacter crescentus. My lab has developed a system to express a wide variety of different anti-HIV proteins on the surface of C. crescentus. These proteins are expressed at very high levels (20% of total cell protein would contain the anti-HIV protein) and we have had no issue with maintaining long term expression. My research is finding new anti-HIV proteins to put on the C. crescentus, and testing two of the most important factors of a microbicide, safety and efficacy. I have to ensure that topical application of the C. crescentus to the vaginal tract will have no adverse effects. I also have to determine how high protection from HIV infection is. My first round of testing indicates that I can decrease HIV infection rates by 85%! This is all done in a test tube, and I will eventually have to move on to testing this in an animal system (see BLT mice blog post). All of this testing (and some side projects that come up along the way) will compose my PhD thesis.

So far, the only downfall of the C. crescentus system is that the microbicide would need to be applied regularly (I haven’t figured out how often yet). The bacteria can’t survive in humans, so protection from infection will be transient. C. crescentus is cheap to grow, so this shouldn’t be cost prohibitive, but the need for reapplication may be a deterrent for clinical use. Indeed, it is believed that adherence to the dosing regime is the reason why the second clinical trial of tenofovir showed no effect.

The development of a microbicide for HIV has the potential to revolutionize the field of HIV prevention. However, there are still a lot of problems in translating laboratory success to clinical success. In the meantime, prevention strategies should focus on testing for infection, condoms, and pre-exposure prophylaxis (when applicable).