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Bringing Down AIDS

After a 30-year battle against AIDS, researchers have discovered vulnerabilities in the virus that may lead to its ultimate defeat.

By Linda Keslar // The MGH Research Issue 2011
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AIDS Achilles heel

Bartholomew Cooke for Proto

Since the emergence of HIV/AIDS as a global health crisis three decades ago, scientists have been striving to develop a vaccine to prevent its spread. The AIDS virus, which infects an estimated 34 million people, is immensely variable and has shown a Houdini-like capacity to escape attack by the human immune system. But during the past two years, researchers in Boston have made notable progress. “HIV is slowly revealing itself,” says Bruce Walker, director of the Ragon Institute, which was established in 2009 as a joint enterprise of MGH, MIT and Harvard University through a $100 million commitment by software executive Terry Ragon and his wife, Susan.

One focus of Walker’s research has been a small group of rare patients, about one in 300 of those infected with HIV, whose immune systems naturally suppress the virus. The ability of these “elite controllers” to keep the HIV infection in check is providing clues for designing vaccines. During the late 1990s, for example, researchers showed that a very high percentage of elite controllers carry a variant form of the HLA gene called B57. Last year, Walker and his Ragon team found that this variant causes the body to make a larger than usual number of potent T cells, white blood cells that help defend against intruders, including the AIDS virus. Patients with HLA-B57 have T cells that are particularly effective at recognizing and killing HIV-infected cells and are more likely to target mutated forms of the virus.

A next step has been to understand how HLA-B57 and other molecules are able to keep the virus in check and, conversely, why other molecules in the same family are less able to do so. In a study conducted with researchers at the Broad Institute—another Harvard-MIT collaboration—Walker and his team compared the genetic makeup of about 1,000 elite controllers with the genes of 2,600 other patients infected with HIV. In subsequent studies led by Florencia Pereyra at Ragon, they found that the differences in the ability of HLA-B57 and others in its gene family to help control HIV involved the “binding pocket” of this family of proteins, a part where pieces of newly formed viruses in infected cells are captured and displayed on the cell’s surface to alert the immune system that an attack is under way. “Of the three billion nucleotides in the human genome, just a handful make the difference between those who can stay healthy in spite of HIV infection and those who, without treatment, will develop AIDS,” Walker says.

In another part of their effort, Ragon researchers earlier this year discovered highly vulnerable regions in the structure of HIV that might serve as vaccine targets. The scientists used a mathematical approach, including a method called random matrix theory, which is used to study stock market fluctuations—it identifies groups of companies whose prices move up or down collectively and those whose rising prices are predictive of others going down. Plugging statistical data about HIV proteins into the model, the researchers identified groups of amino acids that mutate together and pinpointed groups that are least able to tolerate mutations. They compared those findings with their data for elite controllers and discovered that the controllers’ T cells target the same group of amino acids within the virus.

“This study showed us the virus’s weak points, which are what we would like to target,” says Walker, whose team is working to develop a vaccine based on the findings. The institute already has two other vaccines in early clinical trials, one of which Ragon is conducting with the International AIDS Vaccine Initiative, with which it is also collaborating to build a clinical laboratory in Durban, South Africa—a country that has been ravaged by the virus and in which testing can be done relatively cheaply.

The push to develop an effective vaccine comes after decades of largely futile attempts. The only one of the four large-scale trials of HIV vaccines to show even modest success announced its results in 2009, and it cut the risk of HIV infection by just 31% in a group of 16,000 volunteers in Thailand. “We still don’t understand what made the Thai vaccine protective,” Walker says.

Research has shown that both T cells and human antibodies, which battle HIV infection in the blood and in other cells, mass to ward off the virus, often unsuccessfully. But it also may be possible to harness the third way the body tries to fight off infection—its innate immune response, which provides a broad first line of defense against invading organisms.

This past summer, Ragon researchers published a study demonstrating that natural killer cells, part of the innate response, can put immunological pressure on HIV and that the virus tries to evade that pressure. The scientists already knew that NK cells expand during the earliest phase of HIV infection and can suppress HIV replication in tissue culture experiments, but it wasn’t clear whether that happened because the NK cells can actually recognize infected cells and help control viral replication. To study how the virus escaped NK cell activity, a Ragon team led by Marcus Altfeld looked for mutations in the HIV proteins used to evade NK cell responses in 91 people. The scientists found evidence that the virus mutates in response to attack by NK cells, which in turn switches off NK cell responses to the virus.

“This adds a cell to the repertoire of anti-HIV activity,” Altfeld says. “And it raises a number of interesting questions. Now we need a better understanding of the molecular mechanisms that allow NK cells to recognize HIV-infected cells.” Learning how to manipulate NK cells then might become part of the decades-long battle to prevent infection that finally seems to be gaining momentum.

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The Rare Few

Elite Controllers, HIV, AIDS, immunity, Karen Pancheau, Joseph O’Brien

Of every 300 people infected with HIV, one doesn't get AIDS. Understanding this uncanny protection might help science imitate nature.

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