The CD14 C-260T single nucleotide polymorphism (SNP) modulates monocyte/macrophage activation in treated HIV-infected individuals

Abstract

BackgroundHIV-infected individuals have an increased risk of cardiovascular disease (CVD). T-allele carriers of the CD14 C-260T single-nucleotide polymorphism (SNP) have reported increased expression of the LPS-binding receptor, CD14 and inflammation in the general population. Our aim was to explore the relationship of this SNP with monocyte/macrophage activation and inflammation and its association with sub-clinical atherosclerosis in HIV-infected individuals.MethodsPatients with no pre-existing CVD risk factors on suppressive antiretroviral therapy were recruited from University Malaya Medical Centre, Malaysia (n = 84). The CD14 C-260T and TLR4 SNPs, Asp299Gly and Thr399Ile were genotyped and soluble(s) CD14 and sCD163 and high-sensitivity C-reactive protein, hsCRP were measured in plasma. Subclinical atherosclerosis was assessed by measuring carotid intima media thickness (cIMT). The association between CD14 C-260T SNP carriage and cIMT was assessed in a multivariable quantile regression model where a p-value of <0.05 was considered significant.ResultsWe found the CD14 C-260T T-allele in 56% of the cohort and evidence of subclinical atherosclerosis in 27%. TT genotype was associated with higher sCD163 (p = 0.009) but only marginally higher sCD14 (p = 0.209) and no difference in hsCRP (p = 0.296) compared to CC/CT. In multivariable analysis, only Framingham risk score was independently associated with higher cIMT while lower sCD163 was trending towards significance. No association was found in TT-genotype carriers and cIMT measurements.ConclusionThe CD14 C-260T SNP was associated with increased monocyte activation but not systemic inflammation or cIMT in this HIV-infected cohort with low CVD risk profile.

Immunomodulatory Drugs Alter the Metabolism and the Extracellular Release of Soluble Mediators by Normal Monocytes

“…There was a considerable variation among individuals with regard to the levels of the various soluble mediators, and a possible explanation for this could be immunogenetic differences between cell donors. Single nucleotide polymorphisms (SNPs) exist both for NKκB and TLR4 signaling [48][49][50][51][52][53], and certain SNPs seem to be clinically relevant and are associated with differences in regulation of monocyte activation. First, certain polymorphisms have been associated with cancer risk, and this is possibly due to a genotypic influence on intracellular signaling [50,52].…”

“…Second, the risk and/or severity of infections have also been associated with such genetic variants [49,53]. Finally, immunogenetic characteristics may be important for the role of monocytes in the development of inflammations [51,53]. Both clinical and experimental studies suggest that differences in monocyte cytokine responsiveness are important for the associations between immunogenetic differences and severity of infections [53], but differences in TLR4 expression levels may also contribute [48].…”

Polymorphisms in the CD14 and TLR4 genes independently predict CD4+ T-cell recovery in HIV-infected individuals on antiretroviral therapy

“…We have recently examined the relationship of these same polymorphisms and cardiovascular disease in a cohort of individuals on ART recruited in Malaysia [47]. We are currently examining the relationship of these polymorphisms to CD4 recovery but given that this cohort is entirely Asian and they initiated ART late (median CD4 = 63 cells/μL compared to median CD4= 202 cells/μL in this manuscript), we anticipate that the relationship between the polymorphisms and CD4 recovery that we describe here may be quite different.…”

HIV/Human herpesvirus co-infections: Impact on tryptophan-kynurenine pathway and immune reconstitution

“…Whole blood was collected following overnight fasting and plasma separated as previously described [ 35 ]. Plasma samples were stored at -80°C until further analysis.…”