Researchers are testing new approaches to finding a HIV vaccine, but immunosuppression has received surprisingly little attention. (c) 2011, Charlotte Raymond Photography for International AIDS Vaccine Initiative (IAVI)

Like others before him, Jean-Marie Andrieu believes he may have hit upon the long sought after HIV vaccine. And like numerous other treatments under development, the hitch is that the vaccine has only thus far only shown to be effective in protecting monkeys against the Simian Immunodeficiency Virus or SIV, the monkey equivalent to HIV.

Still, Andrieu’s discovery is particularly intriguing in several ways. Whereas vaccines are usually injected into the bloodstream directly, his involves consuming a probiotic enriched elixir. And rather than inducing an immune response capable of destroying the virus, the vaccine works by conditioning the body’s defenses to simply ignore it.

The principle behind deliberately curbing the natural immune response, which doctors refer to as “immunosuppression,” to thwart infection, is a surprisingly sound one. SIV and HIV primarily target CD4 cells, which are programmed to coordinate the attack against foreign invaders. Head off the activation of these helper cells and the virus no longer has a means to replicate and infect the host.

It’s a fairly novel approach that Andrieu and his collaborators admit they’ve only begun to unravel. To date, the Paris-Descartes University medical professor has yet to pinpoint the underlying mechanisms that have enabled his primate test subjects to ward off infection for more than four years, despite repeated exposure to high concentrations of the virus.

“We quite honestly don’t know how the mechanics of how the vaccine works,” he says. “Because diseases have been prevented using anti-bodies and people have only been focused on searching the special antibody, the research community hasn’t come around to the idea that a vaccine doesn’t necessary need to work like that to be effective.”

Normally, vaccines are designed to inoculate populations against specific diseases by modeling the way the body fights off a particular infection, like the measles. Fashioning a reliable vaccine, then, usually involves using a modified or weakened strain to safely illicit a reaction that leads to the production of the same antibodies capable of neutralizing the invader, as well as preventing a re-occurrence.

With HIV and SIV, there’s no such model. Without treatment to control the virus, Andrieu explains, everyone who’s been infected, outside of a few extremely rare exceptions, will eventually succumb to secondary infections. Furthermore, the virus’s propensity to mutate rapidly makes the challenge of developing something that protects across a broad spectrum all the more daunting.

That’s not to say there hasn’t been any progress. In 2009, a team conducting large-scale field trials in Thailand found that volunteers who received an experimental HIV vaccine had a 31 percent lower rate of infection compared to a control group. It’s important to note, however, that some degree of doubt still hangs over whether the reported data indicates true efficacy, especially in light of observations that show the protective nature of the vaccine may wane over time.

And in recent years, biomedical researchers have shifted their efforts more towards developing “therapeutic” vaccines that can be administered to those who were already-infected. While it’s unlikely that such interventions would ever turn into a functional “cure” for patients, there’s evidence that they may help boost the body’s immune response to the virus.

Meanwhile, Andrieu is confident that his unconventional approach will someday open up a new front in the war against a global epidemic that has claimed 36 million lives and counting. His dogged conviction comes from the rationale that attempting to train the immune system to produce a potent HIV-specific antibody would never work, since the virus also hides inside immune cells.

So on a hunch, the French hematologist, along with researchers from the Institut de Recherche pour le Développement in Montpellier and the University of Guangzhou in China, took the opposite tact and began experimenting earnestly with a series of treatments that combined inactivated strains of SIV with various living bacterial agents that, he says, are known to exhibit excellent immunosuppressive properties.

In early trials, “killed” versions of SIV,  in tandem with doses of BCG, were administered to a small subset of 21 Rhesus macaques as either a vaginal gel, a rectal douche or a drink fed through a tube, for a period of five days. The treatment, they found, seemed to confer a lasting immunity against the virus that was later replicated in other sets of monkeys given the dead virus in combination with high concentrations of other bacteria like Lactobacillus plantarum and Lactobacillus rhamnosus — both of which are easily available in pharmacies and certain food products.

And in an unexpected turn, a subsequent diagnostic analysis uncovered no signs of SIV-specific antibodies nor killer T-cells, or as Andrieu puts it: “It was like there was no immune response at all.”

What they did find, though, was a previously unknown class of CD8 immune cells that, in the presence of the virus, appears to halt the activation of CD4 cells. This is done by switching off a set of molecules located on the surface of the cell that are used to detect foreign proteins. Deactivating these molecules, called major histocompatibility complex or MHC, appears to keep CD4 cells in a resting state and impervious to infection.

To verify whether that this was indeed the case, the researchers later injected four of the immunized monkeys with an antibody that eliminates all traces of CD8 cells. As predicted, all were infected during a subsequent exposure to SIV. Fortunately, though, the CD8 cells returned once the antibodies were removed and, in a matter of weeks, viral loads fell back to undetectable levels and remained that way long after.

The initial results were reported in a 2012 and  followed up with a paper published earlier this year in the Journal Frontiers in Immunology. Buoyed by what he’s seen, Andrieu plans to start clinical trials in humans sometime in February or March by the latest. He’ll first test the vaccine on HIV positive volunteers to see whether it disrupts the virus’ replication cycle. If it does — and that’s a big if – then there’s a possibility that the vaccine may work well enough to be used as a “functional cure” that keeps viral loads at undetectable levels.

“Of course, there’s no guarantee of course that it’ll work the same with regard to HIV and people, but I’m confident that it should,” he says. “The important thing is that the new immune cells suppress the CD4 cells only in the instance of SIV. Besides that, it shouldn’t compromise the immune system in any other way.”

The research community has mostly been skeptical of Andrieu’s work and the radical nature of his methods. It’s also often pointed out that, despite some similarities, there’s considerable variability between how HIV infection take hold and progress in human bodies compared to the way SIV affects monkeys. Such complications are most glaringly evident by the failure of numerous once-promising treatments, like the now- infamous Merck STEP trial, to make that vitally important leap from controlled experiments in animal models to reliably duplicating the same level of efficacy among more complex human populations.

But in what has so far been a long, exhaustive search, glimmers of a potential breakthrough can still be sufficient cause for optimism. Just recently, Oregon Health & Science University AIDS researcher Louis Picker was awarded a $25 million by the Gates foundation to further development on a vaccine that cleared Rhesus macaques infected with SIV of the virus. He’s aiming to embark on human trials sometime in 2015.

In an accompanying editorial, Jose Esparza, a leading HIV vaccine researcher and a professor at the University of Maryland’s Institute of Human Virology in Baltimore, handed Andrieu and his team a much needed vote of confidence, even going so far as remarking that the levels of protection achieved appeared “impressive” and that he’d like to see more support for bold projects that take a “out-of-the-paradigm approach.”

“No stone should remain unturned in its search, and the approach reported in this journal should not be dismissed a priori. Instead, it should be carefully considered by other scientists and appropriately confirmed or refuted by additional research,” he wrote.