According to WHO data, 2009 saw 33.9 million people worldwide infected with the human immunodeficiency virus - HIV and of these, 1.8 million died from AIDS while 2.9 million were newly infected with the virus. This leaves a year-on-year increase of just over 1 million HIV positive people of which, many of these will go on to pass the virus. Therefore any strategy to eliminate HIV from the human population will have to aim at both treating those already infected as well as preventing new viral transmission and if this is achieved, HIV infection worldwide would dramatically decrease with every year, severely reducing the global health burden caused by this viral pandemic. The only problem is, how can we successfully prevent transmission?
|Despite a significant decrease the number of people infected by HIV continues to grow year on year|
HIV entry and pathogenesis - where and how can we target it?
One of the major routes of HIV transmission is through sexual activity: an HIV positive person will be carrying many copies of the HIV genome within their cells and in turn these will be able to generate new infectious virus particles. These virions - either present in blood or semen - may be mechanically transferred from infected to uninfected people during sexual activity and many immune cells (Langerhans cells, macrophages and intraepithelial CD4+ T cells to be precise - see below) lining and within the mucosal epithelial surfaces of the reproductive tract are the initial target cells for HIV entry into the human body. It is here that the cells are exposed to the virus through sexual contact, facilitating virus uptake and initial infection then allowing the virus to spread within the body and potentially set up the chronic infection that may develop into AIDS.
|HIV entry via immune cells within the vaginal mucosa and spread to systemic lymphoid organs. Miller, 2007.|
Many potential strategies are currently in development which aim at preventing person-person transmission during sexual activity through the inhibition of HIV particle transfer. This is the reason why condoms - male and female - are so effective. As the authors of the paper outlined below highlight the requirements of such a strategy:
Bacterial symbiosis to the helpIn many cultural settings, women need a product that can be used covertly without obtaining the permission of their sexual partner. In addition, the cost of HIV prevention must be affordable to the developing world. Thus, there is still a need for products that block HIV transmission, are safe and easy to use, and are coitally independent, discreet, and cost effective.
All being so, our bodies are not completely defenseless when it comes to preventing sexually transmitted infections, including HIV; we have multiple tricks up our sleeves and one of which is through a form of bacterial symbiosis. The human reproductive tract is covered in a bacterial biofilm composed of a few species of bacteria, predominantly Lactobacilli. These microbes regulate vaginal biology and aid in the protection against variable infections through the formation of a physical barrier and through alterations in pH. But of course it isn't enough and as I mentioned earlier, people are all too often getting infected with HIV. Yet what if we could enhance these bacterial defenses through genetically engineering those bacteria that natural colonise the reproductive tract? This is exactly what a recently published paper in Mucosal Immunology reports - the development of a novel genetically engineered live bacterial strain expressing an anti-HIV protein that can be easily applied to the vagina and prevents HIV transmission
The group had previously generated an engineered strain of Lactobacillus jensenii (termed:1153-1666) that expressed and secreted a modified Cyanovirin-N (CV-N) protein. This protein has been shown to have a broad inhibitory activity against a range of HIV-1 strains and provide protection from infection in a non-human primate model of HIV through inhibiting virus entry into those target immune cells - it is also highly potent and non-toxic. To establish the potential for administering this bacteria in humans, the group inoculated the vaginas of non-human primate macaques on a regular basis and achieved stable colonisation along with expression of the antiviral protein in the fluid lining the tract; the recombinant L. jensenii was detected along the epithelium while no tissue changes were observed and no untoward inflammation was detected, all indicating the safety of this strategy.
|in vitro HIV inhibition with non-recombinant (left) and recombinant (right) bacteria|
So far, the ability of this recombinant bacteria to inhibit HIV infection has not been addressed so later it was assessed through the use of an in vitro model that accurately portrays the physical and biological architecture of the human vagina as well as the macaque model that uses chimeric human/simian immunodeficiency virus infection. Colonization of the in vitro vaginal tract with the non-recombinant bacteria resulted in a 23% reduction in HIV infection compared to the control while inoculation with the CV-N expressing strain gave 72% inhibition (see above). Groups of macaques were then treated with an antibiotic to remove any endogenous Lactobacillus colonizing their vaginal tract and were subsequently inoculated repeatedly with the recombinant strain. These monkeys were then repeatedly challenged with the virus in a manner similiar to what would happen under natural human conditions and the ability of the virus to infect each animal was assessed over time. This strategy reduced the infection rate by nearly 63% (see below).
|Macaque challenge outline and results of bacterial colonization protection|
This group has generated a bacterial strain - closely related to that already present within the human reproductive tract - that has been genetically augmented through the introduction of the gene for a potent HIV-inhibitory protein Cyanovirin-N. This recombinant bacteria can be inoculated into the vagina and affords protection against initial HIV infection in an in vitro and in vivo macaque model through the expression and secretion of CV-N without generating a toxic response; this engineered microbe is thus better at preventing infection that the non-CV-N expressing bacteria. It remains stable over time But, how then would this function in the real world?
In order to halt the HIV pandemic, we require an at least partially effective strategy to prevent person-person transmission of the virus and this method must safe and inexpensive if it is to be administered to the many people who require it across the developing world. This method outlined above - pending the results of further clinical work - highlights the importance of novel strategies to combat HIV spread. The group outlines the development of an easy-to-apply, safe, efficacious and cheap method to combat HIV transmission in two model systems. Despite these pleasing results, further work will need to be carried out in a clinical field trial to determine whether this mode of protection will work in the real world.
Lagenaur, L., Sanders-Beer, B., Brichacek, B., Pal, R., Liu, X., Liu, Y., Yu, R., Venzon, D., Lee, P., & Hamer, D. (2011). Prevention of vaginal SHIV transmission in macaques by a live recombinant Lactobacillus Mucosal Immunology DOI: 10.1038/mi.2011.30