The role of chemokine C-C motif ligand 2 genotype and cerebrospinal fluid chemokine C-C motif ligand 2 in neurocognition among HIV-infected patients

Objectives: We examined interrelationships between chemokine C-C motif ligand 2 (CCL2) genotype and expression of inflammatory markers in the cerebrospinal fluid (CSF), plasma viral load, CD4 cell count and neurocognitive functioning among HIVinfected adults. We hypothesized that HIV-positive carriers of the risk' CCL2 -2578G allele, caused by a single nucleotide polymorphism (SNP) at rs1024611, would have a higher concentration of CCL2 in CSF, and that CSF CCL2 would be associated with both higher concentrations of other proinflammatory markers in CSF and worse neurocognitive functioning. Design: A cross-sectional study of 145 HIV-infected individuals enrolled in the National NeuroAIDS Tissue Consortium cohort for whom genotyping, CSF and neurocognitive data were available. Methods: Genomic DNA was extracted from peripheral blood mononuclear cells and/ or frozen tissue specimens. CSF levels of CCL2, interleukin (IL)-2, IL-6, tumour necrosis factor-alpha (TNF-a), interferon-gamma (IFN-g), soluble tumor necrosis factor receptor 2, sIL-6Ra, sIL-2, sCD14 and B-cell activating factor were quantified. Neurocognitive functioning was measured using a comprehensive battery of neuropsychological tests. Results: Carriers of the CCL2 -2578G allele had a significantly higher concentration of CCL2 in CSF. CSF CCL2 level was positively and significantly associated with other CSF neuroinflammatory markers and worse cognitive functioning. There was a significant association between genotype and plasma viral load, such that carriers of the CCL2 - 2578G allele with high viral load expressed greater levels of CCL2 and had higher neurocognitive deficit scores than other genotype/viral load groups. Conclusion: Individuals with the CCL2 -2578G allele had higher levels of CCL2 in CSF, which was associated with increased pro-inflammatory markers in CSF and worse neurocognitive functioning. The results highlight the potential role of intermediate phenotypes in studies of genotype and cognition.