Copies count copy number variation in CCLL a natural ligand of CCR and HIV disease

A landmark study by Ahuja and colleagues was published in the journal Science in 2005 showing that the number of copies of a gene possessed by an individual could be a major determinant of susceptibility to an infectious disease (Section 4.5) (Gonzalez et al. 2005). Copy number variation in the segmental duplication that contains the chemokine gene, CCL3LT, was shown to be strongly associated with susceptibility to HIV-1 and the rate of disease progression. Copy number varied significantly between populations and the effect was only apparent when the copy number for an individual was considered with respect to the median for the ancestral population of that individual.

CCL3L1 (also known as MIP1aP and LD78P) is found on the long arm of chromosome 17, together with CCL4LT, and these genes are thought to represent segmental duplications of neighbouring genes CCL3 and CCL4. Unlike CCL3 and CCL4, for which only two copies of each are found in the diploid genome, CCL3L1 and CC4L1 are present at variable numbers in a population, being found at frequencies of one to six copies per diploid genome in Caucasians and in some individuals are absent altogether (Townson et al. 2002).

CCL3L1 was found to have a high affinity for chemokine receptors, notably CCR5, being significantly greater than CCL3 or RANTES such that it is thought to be the most potent ligand of CCR5, and the ligand with the most potent HIV suppressive effects (Nibbs et al. 1999). CCL3L1 significantly inhibited infection of peripheral blood mononuclear cells by HIV-1 strains which used CCR5 (Menten et al. 1999) and had potent antiviral activity in macrophages (Aquaro et al. 2001). The truncated form of CCL3L1, naturally produced by the lymphocyte surface glycoprotein and protease CD26, had even higher affinity for CCR1 and CCR5 receptors (Proost et al. 2000). CCL3L1 is thus a highly active natural HIV entry inhibitor.

Given the reported variation in copy number of CCL3L1 and its potent HIV suppressing activity, Ahuja and colleagues investigated the relationship between copy number and disease susceptibility (Gonzalez et al. 2005). They first studied how copy number varied within and between populations of different geographic and ethnic origin. It was a large study group, 1064 people from 57 populations, as well as 83 chimpanzees. This showed clear variation between populations, notably between African and non-Africans with an average of four copies of CCL3L1 in Africans and two in non-Africans. The investigators proceeded to study large cohorts of more than 5000 HIV infected and uninfected people and clearly showed that CCL3L1 copy number was a major determinant of susceptibility to HIV-1 for an individual when compared to the median for their ancestral population. This was true for individuals infected by mother-to-child transmission and adult-to-adult transmission: with a copy number lower than the median, risk was higher; at copy numbers higher than the median, the risk fell in a dose-dependent stepwise fashion for the cohort of children exposed perinatally to HIV-1. For each copy of the CCL3L1 gene, the risk of acquiring HIV-1 reduced by 4.5-10.5% depending on the specific population studied. Overall, HIV positive persons had lower CCL3L1 copy numbers than uninfected people. Moreover the rate of disease progression was also associated with copy number: at a lower gene dosage than the median for the cohort or population there was a dose-dependent increased risk of faster progression to AIDS or death.

When CCL3L1 copy number variants were analysed together with the known disease associated variants of CCR5, the authors estimated that variation in these factors accounted for up to 42% of the burden of HIV/AIDS and 30% of the accelerated rate of progression to AIDS (Gonzalez et al. 2005). It is thus postulated that in the presence of increased copies of CCL3L1 there is greater binding of the encoded chemokine to the CCR5 receptor, reducing the amount of CCR5 accessible to HIV-1 on the surface of leukocytes.

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