Published online 4 November 2010 | Nature | doi:10.1038/news.2010.582

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Worldwide study implicates structural changes in a protein binding site

Tiny changes to the structure of the HLA-B protein confer immunity to HIV P. de Bakker

Why do some people who are infected with HIV not go on to develop AIDS? A large-scale genetic analysis1 suggests that the answer lies in tiny changes in the structure of a protein that helps the immune system to recognize and destroy infected cells.

Most people who contract HIV eventually end up with full-blown AIDS as the virus replicates in their cells, reaching very high levels and damaging their immune systems. However, the virus does not progress to this stage in about 1 out of every 300 infected people. These 'HIV controllers' do not require treatment, because their bodies suppress the replication of the virus.

Bruce Walker, an immunologist and director of the Ragon Institute of Massachusetts General Hospital, the Massachusetts Institute of Technology and Harvard University in Charlestown, first thought of carrying out the study when he recognized the clinical value of such HIV controllers. "I realized that we could create a cohort by going directly to physicians around the world, and I thought we should figure out what is genetically unique about people who do well compared with people who do badly," he says.

Hunting for variations

Walker and his colleagues sampled the DNA of more than 900 HIV controllers. They compared it with the genetic code of 2,600 individuals with normal HIV infections, using a technique called a genome-wide association study (GWAS). The GWAS tested single nucleotide polymorphism (SNP) variations — changes in one letter of DNA — at a million points in the genomes of these individuals, and found more than 300 sites that were statistically associated with control of HIV.

All the sites identified are in a region of the genome that codes for proteins involved in immune response, called HLA proteins. The researchers used regression analyses to narrow their search down to the four sites most strongly linked to HIV immunity.

“This will help us induce better responses to HIV, because we now know what it is that we're trying to induce.” Bruce Walker

Ragon Institute of Massachusetts General Hospital

It isn't possible to tell from the statistics alone whether these sites cause HIV immunity themselves or are simply closely associated with others that do. But using a detailed map of the HLA regions of the genome, created as part of an earlier diabetes study2, the team pinpointed specific amino acids in the protein HLA-B that differed between controllers and people with normal infections. These amino acids seemed to be behind the ability to control the virus. "Out of the three billion nucleotides [that make up the human genome], we narrowed it down to a handful of amino acids that define the difference, each coded for by just three nucleotides," says Walker.

HLA-B plays an important part in the body's immune response to viral attack. When viruses infect the body, they hijack host cells to produce viral proteins. HLA-B grabs peptides — short fragments of these viral proteins — and carries them to the cell membrane, where they act as markers to flag the cell for destruction by the immune system. Five of six amino acids that differed between controllers and non-controllers are found in the lining of the structural pocket used by HLA-B to bind those viral proteins.

A smaller study in South Africa3 had already implicated HLA-B in HIV immunity, but "this confirms that HLA-B is the most important protein", says Rodney Phillips, an immunologist and co-director of the Institute of Emerging Infections at the University of Oxford, UK.

The mechanics of immunity

Changes in the amino acids identified by Walker's team alter how HLA-B presents viral peptides from HIV to the immune system, but how this process differs between controllers and people with normal HIV infections remains unclear. "We're trying to define the precise mechanism and figure out exactly what this thing is doing, so there is clearly more work to be done," says Walker.

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Studies of immune responses to other diseases have also implicated amino acids in the binding pocket of HLA proteins, says Phillips. "If you've got a slightly different structure to the groove, you may be able to bind peptides in a slightly different sequence, or at a slightly different [protein-folding] conformation, and that might evoke a better immune response," he says.

However, it will be a long time before this work gives rise to treatments or vaccines. "We're a long way from translating this, but the exciting part is that this GWAS led us to an immune response. That has to be good news for vaccines, because they manipulate the immune response," says Walker. "We're cautiously optimistic that this will help us develop ways of inducing better responses, because we now know what it is that we're trying to induce."