Genetic study shows how HIV controllers get their groove

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The vast majority of people who are infected with HIV go on to develop AIDS. Their bodies become riddled with the virus, their immune systems falter, and they are besieged by life-threatening infections. But not everyone shares the same fate. Around 1 in every 300 people infected with HIV carry genetic trump cards that allow them to resist and control the virus. These “HIV controllers” can live with the virus for years. They never develop AIDS and they live long, healthy lives, even if they never take any medication. Their genetic secrets are slowly being revealed.

Since 2006, a massive group of international scientists have been recruiting and studying a large group of HIV controllers from around the world as part of the International HIV Controllers Study. All of the recruits have been HIV-positive for 10 years. Despite that, the levels of the virus in their blood are around 50 times lower than expected and they have healthy levels of helper T cells, the immune cells that are normally hit by HIV.

Led by Florencia Pereyra, Xiaoming Jia and Paul McLaren, the team compared the genes of almost 1,000 controllers with those of over 2,600 people who haven’t been so lucky at subjugating the virus. After looking at over 1.3 million points around their genomes, the team found that just 313 separate the controllers from the other recruits.

Amazingly, every single one of these variants sits within a specific part of our sixth chromosome, among a set of genes called class I HLA genes. The proteins they produce form part of the internal security checks that defend us from infections. They grab small pieces of other proteins from inside our cells and display them on the outside, waving them under the noses of passing T-cells. If the T-cells recognise these pieces as parts of bacteria, viruses or other foreign invaders, they tell the infected cell to self-destruct and set the immune system on red alert.

All of this depends on a single groove in the HLA proteins. This is the bit that embraces the pieces of other proteins and displays them so prominently to the immune system. If this groove isn’t structured correctly, our defenders don’t get an advanced warning about threats.

True enough, the team found that the groove of a single protein called HLA-B is especially important. At five positions in the groove, the HIV controllers have different amino acids than those whose disease progresses normally. These five amino acids aren’t the only things separating the controllers from the others, but they have a major impact. One of them – the one at position 97 – is “associated with the most extremes of viral load” depending on the… amino acid [there].”

The link between these amino acids and the control of HIV is also very consistent. Pereyra did her protein comparisons using only the Europeans in her study (who formed the largest proportion of the sample). However, the results held true when she focused on the African-American group, and when she repeated the comparison in an independent group of HIV-infected Swiss patients. Again, people with different amino acids at certain key spots in HLA-B  proteins were more likely to keep the virus at bay.

It’s still not clear how exactly these genetic variations alter the shape of the HLA proteins, and how these changes affect the ability to control HIV. Nonetheless, the international study is off to a promising start and perhaps, it will help to inspire future vaccines or treatments against this most frustrating of foes.

Reference: Science http://dx.doi.org/10.1126/science.1195271
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