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.)