Among the ambitious undertakings at the Bill & Melinda Gates Foundation is the Grand Challenges Explorations grant program which seeks radical new approaches for vanquishing infectious diseases that are global scourges.

The first cycle of the process culled 35 proposals thought by the foundation to have particular promise as break-out ideas for beating HIV, which has so far withstood massive and concerted scientific efforts to develop a vaccine. Even to the layperson, these Explorations clearly span a remarkable range of approaches, from efforts to augment the body’s own defenses to engineering completely synthetic ones.

Brief profiles of the Explorations follow, drawn from interviews with grantees and the Gates Foundation. There are few stabs at vaccines promising full immunity, such as George Dickson’s "Trojan horse" vaccine under construction at University of London, which he hopes will "incorporate into the virus and render it very visible to the immune system," much as the wooden horse allowed the Greeks to throw open the gates of Troy from inside.

Most projects attack HIV at a single point, stifling viral replication or eliminating infected cells, for example. Some amount to variations on previous approaches, but more than a few Explorations are works of surpassing human ingenuity, reinvigorating the contest between 21st century science and a virus perhaps seven million years old. The paradigm shift here could be described as a move away from mobilizing for war with HIV and towards détente.

Once more into the breach

HIV is armored by a shield of sugars and proteins known as the gp120 envelope, which repulses the immune system’s efforts to bind to and disable the virus. Once HIV starts replicating in the body, a high mutation rate makes the gp120 envelope a shape-shifter — and the immune system is forever bringing a square peg to fit a round hole.

As many as 5,000 research papers have been written about the gp120 envelope. The heavy guns of big science remain trained on it. Elucidating the envelope is a major objective of a team led by Joseph Sodroski as part of the $300 million Center for HIV-AIDS Vaccine Immunology (CHAVI). Regarding the amount of progress on his task, a circumspect Sodroski comments: "Without putting numbers on it, let’s just say we only know a little and what we do know isn’t enough."

Enter five researchers clutching $100,000 Explorations grants and wielding ideas for breaching gp120’s defenses:

Pandelakis Koni at the Medical College of Georgia hopes to exploit recent discoveries in mice to develop antibodies capable of binding to the sugary carbohydrate portion of the HIV envelope. Similarly, Abraham Pinter at the University of Medicine and Dentistry of New Jersey is hoping to "unmask" hidden vulnerabilities in the carbohydrate portion of the gp120 shield. In another borrowing from the animal kingdom, Jord Stam at Utrecht University in the Netherlands will use llama antibodies to develop two-sided antibodies, one side attaching to the virus, the other dragging it off to where it cannot replicate. In a mostly synthetic approach, Johnny He at Indiana University is fabricating biodegradable nanoparticles to capture roving viruses and infected cells.

By contrast, Nancy Haigwood hasn’t given up on the human immune system. Haigwood, at Oregon Health & Science University, points out that some people’s immune response somehow tames mutation of the virus, causing it to fall into a pattern which makes it vulnerable to antibody defenses. Haigwood is working on a vaccine based on the strains of the virus from people whose immune systems successfully reined in mutation.

Friendly fire

If unable to defeat free virus marauding in the bloodstream, researchers hope to prevent it from invading cells. The virus docks — effortlessly and implacably — at a location known as the CCR5 receptor site. So a number of Explorations attempt to take away the site or block it. People who lack the genes for CCR5 — roughly 1% of the population — are essentially immune to HIV. Occurrence of this mutation is highest in northern Europe; people of Asian, African and South American descent almost never carry it. (Indeed a cancer patient was recently "cured" of AIDS after receiving a bone marrow transplant from a donor bearing the rare genetic trait. )

However, bone marrow transplants cost hundreds of thousands of dollars. The Gates Foundation hopes the India-based company, Pondicherry Biotech, can "achieve targeted disruption of CCR5 genes," perhaps using genetically engineered, transplantable stem cells. In more of a blockade strategy, Benjamin Chain at University College London is developing antibodies to contend with HIV for the CCR5 receptor. The question is whether such antibodies can out-compete the virus without themselves triggering a potentially very damaging autoimmune response.

Some primates have very successfully combated the simian version of HIV, possibly because of immune defenses around the CCR5 receptor. Zhiwei Chen at the University of Hong Kong plans to investigate whether presenting the immune system with a foreign version of the CCR5 receptor, a variant one from one of our primate relatives, might summon a response that would protect against HIV, a project that’s a long shot and presents significant safety issues.

Battles metaphorical and molecular

There are more than 30 million people already infected by HIV and today their best hope is to fend off AIDS by taking antiretroviral drugs for the rest of their lives. A number of the Explorations seek something closer to a cure.

Ralph Albrecht at the University of Wisconsin hopes to raze HIV-infected cells using swarms of nanoparticles. Once the gold-clad hunters have attached to HIV-harboring cells, a magnetic field will be used to heat their magnetite cores, melting holes in the walls of infected cells, killing them. Albrecht envisions a device a bit like the security sniffers at airports for generating the requisite magnetic effects. The technique is borrowed from efforts, just entering human trials, to "cook" cancer tumors. Thus far, Albrecht has gotten his approach to work on HIV in a test tube and now will see if it can be made to work on infected cells.

Ideally the body’s own T cells would perform this task — and might yet with a little assistance. Some individuals with HIV, dubbed "long-term non-progressors," mount a more effective immune response, including T cells able to recognize HIV-infected cells. Altor Bioscience, one of six private companies funded by the Explorations, is working to engineer these more efficacious T cells which will be joined to a "payload" for destroying infected cells.

Stephen Johnston and Douglas Nixon have a completely different idea for hunting down infected cells. Johnston, at Arizona State University, catchily describes his scheme as "preventing HIV backwards." HIV-infected cells produce proteins different from those of healthy cells. Both Nixon and Johnston (separately) seek to immunize against those stable, unchanging proteins rather than the bewildering, kaleidoscopic array of HIV products.

Tadataka Yamada, Gates Foundation president for global health, praised this approach for challenging existing dogma. Ironically, Nixon and Johnston, both past their 30s, also provide counter-evidence to concerns at the foundation and elsewhere that the graying of the researcher population necessarily explains a lack of breakthrough thinking.

Nixon and Johnston, however, are typical of Explorations winners in that both are veterans in their field. Although the Explorations represent a sort of open tryout, it’s the pros who are overwhelmingly filling out the team, at least in the first round. Of the 35 HIV-related grantees, one in four is new to the disease area while others have been in the field practically from its inception. On average, these 35 grantees published their first paper on HIV eight years ago, so they bring considerable expertise, even though the foundation inveighed against "anointed experts" when inviting applicants. (Perhaps as with perennial disapproval of Congress, it’s the candidates that other people anoint who are responsible for the disappointing results.)

Strand-to-strand combat

Researchers are looking for ways, inside the cell, to stop the prolific virus from pouring forth deadly variants of itself. HIV cleverly decommissions a cellular sentinel — a protein called APOBEC3G —which normally disarms the virus. Harold Smith, professor at the University of Rochester, building on 18 years and $6 million of NIH-funded research, believes he can find a way to reactivate APOBEC3G.

In a kind of biological jujitsu, Yale’s Karen Anderson hopes to turn HIV’s own power of mutation against itself. Anderson is looking for compounds she hopes will "encourage the virus to make mutations until the virus is annihilated," essentially inserting random keystrokes into its genetic script until it ceases to have biological meaning and viability.

Enzymes called nucleases might also wreak havoc on viruses such as HIV. Ronald Raines at the University of Wisconsin and Keith Jerome of the Fred Hutchinson Cancer Researcher Center are developing different enzymatic shears, based on different nucleases, which they hope will cut HIV’s genetic text to ribbons.

Resistance: futile?

There was once a battle over the cause of ulcers. The establishment camp, then home to the foundation's Tadataka Yamada, believed acid caused ulcers. Arrayed against this "acid Mafia" stood the scrappy proponents of bacteria — who turned out to be right. Yamada has told this story about himself because he hoped the Explorations would churn up big, dogma-busting ideas. Mostly, however, they summoned incredibly clever thinking.

Among the HIV Explorations, the closest thing to a new paradigm is the idea that fighting the virus plays into its hands. Primates like African green monkeys frequently have great quantities of SIV (the simian version of HIV) in their bloodstream. Yet they do not succumb to AIDS. It appears that African green monkeys immune reactions de-escalate, rather than mounting a furious response. Some of the primates with the biggest brains think this approach might work for them.

Monkey see, monkey do

Although the strategy of inducing this tolerance predates the Explorations, getting funding has been difficult. As one researcher put it "I would certainly not be exploring this area without [the] Explorations." A number of researchers have been so enabled. Samuel Landry at Tulane University is examining how HIV might "over-stimulate" the immune system. Once on tilt, it generates only a weak, narrow antibody response. Landry hopes to dampen the overreaction to HIV, he says, "much as one suppresses an allergic response with allergy shots."

Along similar lines, the immunity-suppressing drug Fingolimod helped mice to clear a virus otherwise overwhelming to their systems. According to John Altman at Emory University, Fingolimod appeared to reverse immune-system exhaustion, allowing it to gain control of the infection. He conjectures that perhaps Fingolimod "locks" T cells in lymph nodes away from sites of infection.

But the real test of whether tolerance is superior to the more conventional approaches that build up resistance will be conducted by Barry Peters, of Kings College London. Peters is set to study whether people with calmer immune reactions to HIV infection are ultimately more successful in keeping AIDS at bay.

If tolerance does in fact stave off immune failure, "we will be in a position to look at translating these findings into HIV vaccine strategies," said Peters, who has plans near at hand. The human genome already presents a living record of past virus wars, pocked with battle scars, emblazoned with the DNA of successful viral invaders. Détente with this most recent adversary would not be marked by treaty but an indelible genetic graffito: "HIV was here."

Miocene era 1, 21st century 0

The scale and speed of HIV's damage — it is the world’s fourth biggest killer — can make many of us regard a cure as the only real success. But the other great biological battle of the 20th century, the war on cancer, tells a cautionary tale, one of reduced expectations. After more than three decades and 1.5 million research papers, there is less talk of a cure and more of holding cancer at bay, allowing people to live with the disease as they do other chronic conditions like high blood pressure.

In the foundation's view, a vaccine for HIV presents the hardest scientific challenge, followed by malaria, which in turn is seen as less tractable than tuberculosis. More generally, science, the biological kind, is harder than anyone seems to know or would like to acknowledge.

Inspecting any given scientific frontier in the many-fronted war on disease exposes gaps in knowledge and thin ranks of researchers. Andrew Serazin, Program Officer of the foundation’s Global Health Discovery program, recognizes the seemingly numberless paths that break-out research might take. "Can we identify a specific roadblock or paradigm we're trying to get around?" he asks, and then answers his own question: "There are more of these than we have space for."

The Explorations, in their inaugural round, unearthed good and even some brilliant ideas &mdash all of them longshots. We can still celebrate their daring as well as pause to recognize Gates Foundation's audacity. The Explorations are a conscious, genesis moment, deliberate first threads the foundation hopes will spin over time into a new ribbon of reality.