More genetics done right -- GWAS and HIV controllers

About 1 in 300 people infected with HIV don't go on to develop AIDS. or do so much more slowly than expected -- this has been known for some time.  It was once thought that these people would never develop AIDS, so this subset of people was termed the "long-term non-progressors" but in fact many eventually do develop AIDS, and this group are now called "HIV controllers."

Now The International HIV Controllers Study reports the results of a genomewide association study (GWAS) undertaken to try to determine what is different about HIV controllers compared with those who develop disease (the ScienceExpress paper is here, and a story in The Independent about the report is here).  They included 900 HIV controllers from around the world and 2600 'progressors', people for whom the natural history of HIV infection was as expected. 

Not surprisingly, the significant genetic differences between controllers and progressors were within the major histocompatibility complex (MHC), a part of the immune system that distinguishes self from non-self, self from viruses and bacteria.  Specifically, they found 5 single nucleotide polymorphisms (SNPs) within a stretch of the MHC that codes for HLA-B, a gene for a protein involved in defending against viruses. It presents fragments of HIV on the surface of infected cells, and this presentation is recognized by CD8+ T-cells.  While there is extensive variation in MHC genes among humans, the HLA-B protein in controllers regularly differed from that of progressors by 5 amino acids, which changes the shape of  the protein and how it binds to HIV.  

Altogether, these results link the major genetic impact of host control of HIV-1 to specific amino acids involved in presentation of viral peptides on infected cells. Moreover, they reconcile previously reported SNP and HLA associations with host control and lack of control to specific amino acid positions within the MHC class I peptide binding pocket, where the HIV fragment is 'housed' on presentation. Although variation in the entire HLA protein is involved in the differential response to HIV across HLA allotypes, the major genetic effects are condensed to the positions highlighted in this study, indicating a structural basis for the HLA association with disease progression likely mediated by the conformation of the peptide...

(The illustration is from Wikimedia Commons and is of the backbone structure of HLA-B*5101 complexed with HIV's immunodominant epitope KM2 1e28. Peptide is shown in yellow in the binding pocket. Beta 2 microglobulin is show in the lower left, and membrane attachment site is in the lower right. 3D Structure is derived from Maenaka, K. et al. (2000) Nonstandard peptide binding revealed by crystal structures of HLA-B*5101 complexed with HIV immunodominant epitopes. J.Immunol. 165: 3260-3267)

The authors of the International HIV Controllers Study write that there are other differences between controllers and progressors that may be important in whether or how quickly they progress to disease, but that they believe that the differences they found in the HLA-B gene, and what they mean for viral/peptide interaction, are the most likely explanation.  They are cautious about over interpreting, even when talking to the media, which is not always the case. As quoted in the The Independent:

Dr Walker emphasised that the discovery is not like a "light switch" that turns someone into an HIV controller. It is one factor among several that increases the chances of someone being able to survive for many years with HIV and not antiretroviral treatment, he said.

"We've identified a major determinant but there are other factors that will influence the pathway. We've not identified the precise mechanism to explain HIV controllers but we know that of all the genetic influences involved, this is by far the most important," Dr Walker said.

And they can't yet describe the specifics of how the altered protein works, but that is the focus of current studies, and one can assume that they will ultimately be successful now that the target of investigation is clearer.

As regular MT readers know, we aren't great fans of GWAS in general, but this is one example of a successful study.  This is because the genetic effect is large enough to be detectable. The investigators used clever techniques to dissect out (statistically) the effects of particular variants in the HLA-B gene.  The strongest signal was in an allele called HLA-B*5701.  This was replicated and in fact was the only usefully strong signal in this study.  That shows that GWAS works, because that allele was already known to be involved in slow progression.  Indeed, it's screened for in treating HIV patients because those bearing that allele can over-react to a drug called abacovir (the drug is not used on such patients).  So, one must be tempered about this finding and the usefulness of the GWAS approach.

Beyond this, the study found weak signal (semi-imaginary?) in a CCR5-CCR2 region, where variation has been suggested in other studies to affect HIV sensitivity.  Nothing else in the genome generated any signal.  And these two sites were responsible for 19 and 5 percent of resistance.  So it is a typical GWAS result.  Nonetheless, it focuses attention on the HLA region as 'the' region to think about, at least at this stage.  And it shows that focused, problem-specific GWAS studies can do their job, even if there were other ways to find these genes--why?  because their signal is strong.  And it confirms the general challenge to us, that many genes with minor effect are probably involved here as with other complex traits....what to do about them is the next challenge.

A discussion of the paper in Nature concludes:

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."