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

Abstract

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 HIV-infected 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-α), interferon-gamma (IFN-γ), soluble tumor necrosis factor receptor 2, sIL-6Rα, 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.

Fig. 1. Cerebrospinal fluid chemokine C-C motif ligand 2 levels among carriers and noncarriers of the CCL2 −2578G

CSF samples were analysed for CCL2 expression via multiplex assay. Carriers of the −2578G allele include genotypes GG and GA, while noncarriers containing the −2578A allele include genotype AA. The mean expression level with SEM error bars is shown. P value was calculated by ANOVA.

Fig. 2. CCL2−2578G genotype and plasma viral load on chemokine C-C motif ligand 2 expression and global deficit score

Carriers of the −2578G allele include genotypes GG and GA, while noncarriers containing the −2578A allele include genotype AA. Plasma viral load was measured and groups were separated as high (≥5000 copies/ml) and low (<5000 copies/ml). (a) CSF samples were analysed for CCL2 expression via multiplex assay. The mean expression level with SEM error bars for each group is shown. (b) Global deficit score (GDS) was calculated on the basis of averaging individual test deficit scores. The mean GDS with SEM error bars for each group is shown.