I don't need to convince anyone that HIV is a major health concern, particularly in Africa and (increasingly) East Asia. It's long been known that susceptibility to HIV infection varies between individuals, with some people engaging in high-risk activities for long periods of time nonetheless remaining uninfected. In addition, individuals infected with HIV show considerable variation in the rate at which the disease progresses to full-blown AIDS. This variation is naturally of interest to researchers looking for treatment options: if they can figure out why some people are naturally resistant to the virus, that may help to find ways to help other people fight off infection.Variation in susceptibility to HIV is at least partly genetic, but the specific protective variants identified to date - most notably the CCR5 Δ32 polymorphism, and variation in the HLA region - are thought to capture only a small proportion of the total genetic variation. For instance, a recent genome-wide scan for genetic variants that influence viral load in people infected with HIV that have not yet progressed to full-blown AIDS identified variants that explain only 15% of the total variation in infection risk. It's likely that several other genetic variants of moderate effect are still out there, and with that in mind a new study published in PLoS Biology used a different approach to look for other genetic regions that influence HIV susceptibility.
In their first series of experiments, the authors avoided the messiness of dealing with live human beings - who differ from one another with respect to their behaviour, their degree of exposure to HIV and the strains of HIV they encounter, in addition to their genes. Instead, they looked at a simplified model of HIV infection involving white blood cells (B and T cells) grown in the lab.
The study first used B cells derived from 198 individuals from 15 multi-generation families. They infected each of the cell lines with a modified version of HIV and tested how susceptible each line was to infection. As expected, there was considerable variation in susceptibility, and that variation was substantially genetic - the authors estimate that around half of the variance in susceptibility was genetically determined.
The authors then tested markers from throughout the genomes of these cell lines to find the specific regions of the genome that correlated with this variation in susceptibility. This approach identified a novel region on chromosome 8, around the SNP marker known as rs2572886: the "susceptible" version of this polymorphism was associated with a 1.6-fold increase in susceptibility to HIV infection in a separate experiment on T cells (the usual hosts of HIV in the human body).
Of course, the big question is whether an increased susceptibility in isolated cells translates into increased susceptibility in real live humans. The authors attempted to address this, but their results are tentative at best: of the two (relatively small) groups of humans they examined, one showed a slightly greater increase in viral load and a slightly greater decrease in white blood cell count over time for carriers of the "susceptible" version, while the second cohort showed no association at all. Pooling the two cohorts resulted in no significant association overall.
No doubt we will see follow-up studies in larger human groups over the next couple of years that should provide more definitive answers - until then, the authors admit, "this association should be considered suggestive".
The authors make a valiant but ultimately fruitless attempt to pin down the function of their polymorphism, which unfortunately rests in the middle of a large region of the genome containing no known genes. They show somewhat sketchy evidence that the region containing their variant physically associates with regions in other, quite distant genes, suggesting that it may play a role in regulating the expression of these genes. Unfortunately these genes are expressed at low levels, making it difficult to test this hypothesis directly, and experiments to look at the effects of disrupting these genes on HIV infection susceptibility were inconclusive.
How important is this new marker compared to previously identified genetic determinants? Thoughtfully, the authors actually provide estimates of the proportion of variance explained by each of the known markers, using their own data-set. This comparison certainly puts their results in perspective: their new marker explains less than 1% of the variance in white blood cell count and viral load, while the three major markers identified in the previous genome-wide scan explain between 5.8 and 9.6% of the variance each. The well-known CCR5 Δ32 polymorphism also ranks fairly poorly, explaining between 0.4 and 1.9% of the variance.
Where is the remaining variation hiding? It's likely to rest in two places that are largely inaccessible to the current generation of SNP chips: rare variants of moderate to large effect, and copy number variations (CNVs - that is, insertions and deletions of regions of DNA). Accessing this variation will require a combination of sequencing and the use of new chips for detecting CNVs. Ideally, such studies should also be carried out in individuals of African ancestry, since African populations are currently experiencing the greatest impact of HIV, and it's highly likely that susceptibility alleles will differ between African and European groups.
While the results of this study are far from conclusive, the authors deserve praise for a clever and thorough experimental strategy, combining genome-wide data from cultured cells, validation studies in human cohorts, and functional studies. This combined approach is likely to become more and more common as the "low-hanging fruit" - that is, the common variants with large effect on disease risk - are picked off by simple genome-wide association studies, and journal reviewers start to demand higher levels of evidence to support new associations.
(Image of HIV-infected white cells courtesy of Stanford University.)
Loeuillet, C., Deutsch, S., Ciuffi, A., Robyr, D., Taffé, P., Muñoz, M., Beckmann, J.S., Antonarakis, S.E., Telenti, A. (2008). In Vitro Whole-Genome Analysis Identifies a Susceptibility Locus for HIV-1. PLoS Biology, 6(2), e32. DOI: 10.1371/journal.pbio.0060032
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