An inherited genetic variation of a protein that HIV can use to attach to cells, known as the CX3CR1 249I polymorphism, may partially explain long-term non-progression, according to Spanish researchers. If these results, which are published in the December 15th issue of the Journal of Acquired Immune Deficiency Syndrome (now available online), are validated through further research, this may eventually lead to another class of co-receptor antagonists alongside the CCR5 and CXCR4 inhibitors currently in development.
In addition to the CD4 receptor, HIV must also bind to other receptors on the surface of any cell it wants to infect, and these are called 'co-receptors'. The most common HIV co-receptors are CCR5 and CXCR4. However, in 1998, CX3CR1 - which normally acts as a receptor for the naturally-occurring body chemical (or chemokine) fractaline - was also identified as an HIV co-receptor.
Most of the studies of CX3CR1 that have been done so far have been in people who have progressed rapidly, but researchers in the Spanish Catalonia region were interested in examining long-term non-progressors to see whether certain inherited variations within the CX3CR1 gene might make a difference to disease progression.
This multicentre observational case-control study recruited 271 participants from a pool of over 3000 HIV-positive individuals from five different hospitals in Catalonia. This included 60 long-term non-progressors who had been infected with HIV for more than 15 years; had never taken any antiretrovirals; had a stable CD4 cell count persistently over 500 cells/mm3 and a viral load repeatedly below 5000 copies/mL. Another 109 HIV-positive people whose HIV disease progressed as 'normal', as well as 102 HIV-negative 'controls' were also studied.
Everyone in the study was a white Spaniard, and apart from the duration of HIV infection, CD4 count and viral load (which were bound to be different due to the entry criteria differences between long-term non-progressors and 'normal' progressors), demographic characteristics were similar between all three groups: the majority were male and aged in their early 40s, and the majority of HIV infections had been via injection drug use.
The researchers looked for two different genetic variations within CX3CR1, 280M and 249I. Each gene has two parts to it, inherited from each parent, known as alleles, represented by a letter of the alphabet. These alleles may be the same (e.g. GG, AA) or may be different from one another (GA). In the case of CX3CR1, two distinct genetic variations, or mutations, have been previously reported: at position 280 within the chain of amino acids that make up CX3CR1 (where there are T's instead of C's, known as the 280M mutation) and at position 249 (where there are A's instead of G's, known as the 249I mutation).
The researchers found no significant differences between the three groups for the 280M mutation.
However, although they found no differences between those who were HIV-negative and HIV-positive for the 249I mutation (suggesting that this mutation does not protect against HIV infection), they did find that there were significant differences between the HIV-positive long-term non-progressors and the 'normal' progressors.
In the case of long-term non-progressors, they were significantly more likely to have A's rather than G's than the 'normal' progressors (odds ratio: 0.46; 95% CI: 0.27 to 0.75). This significance remained even after excluding the 45 individuals who had the CCR5 delta 32 mutation, which is also thought to be partially protective against HIV disease progression.
They also found that a combination of the 249I mutation along with the 280M mutation was inherited more often in long-term non-progressors, compared with the 'normal' progressors (p = 0.0007). In addition, everyone with the 280M mutation inherited the 249I mutation, but it was possible for the 249I mutation to be inherited on its own.
In their discussion the researchers admit that although results of their study suggest that individuals with the 249I mutation appear to have some protection against HIV disease progression, it can only provide part of the picture because not all long-term non-progressors had this mutation, and not all 'normal' progressors were without it.
They also note that the frequency of 249I found in their study (24.5% of 'normal' progressors, 35% of HIV-negative 'controls' and 42% of long-term non-progressors) is higher than reported in other studies that have looked for 249I as a factor in HIV disease progression. This may be due to the fact that they only looked at 'pure' Spanish genes which may have "genuine genetic diversity due to migration patterns and the occupation of Spain historically by eastern populations", but also may be because their definition of a long-term non-progressor was different from other studies' definitions, particularly in terms of length of HIV infection.
The researchers conclude that "our results suggest that CX3CR1 V249I polymorphism partly explains the diversity of HIV-1 disease progression among individuals", but that further studies are needed to validate their findings. "If so, our results would then provide an insight for continued investigation of this chemokine receptor as a possible target for future antiretroviral drugs."
Vidal, F et al. Spanish HIV-1-Infected Long-Term Nonprogressors of More Than 15 Years Have an Increased Frequency of the CX3CR1 249I Variant Allele. Journal of Acquired Immune Deficiency Syndromes 40(5): 527-531, 2005.