Polymorphisms in toll-like receptors influence susceptibility to HIV infection and its clinical course
Abstract number: o396
Bochud P.-Y., Hersberger M., Taffé P., Bochud M., Stein C., Calandra T., Francioli P., Telenti A., Speck R.F., Aderem A., & The Swiss HIV Cohort Study
Toll-like receptors (TLRs) have a key role in innate immunity and participate to antiviral defence mechanisms. We examined whether single nucleotide polymorphisms (SNPs) in TLRs 2, 3, 4, 7, 8 & 9 influence susceptibility or the course of HIV infection in the Swiss HIV Cohort.
28 SNPs in TLRs were analysed in 1255 HAART naive HIV+ patients (cases) & 128 blood donors (controls) using the Sequenom technology. The distribution of SNPs frequencies was compared between cases and controls. In HIV+ patients, the CD4+ T-cell decline was calculated using a least squares regression line and a model using a latent variable. The impact of TLRs SNPs on CD4 cells decline and HIV RNA was evaluated using a linear regression model. A logistic regression model was used to estimate the risk associated with SNPs comparing rapid progressors (slope < percentile 15) and slow progressors (slopes > percentile 85) to others patients.
3 SNPs in TLR8 that are in linkage disequilibrium [C645T (H215H), G1953C (L651L) and C2253A (I751I)] were more frequent in HIV+ patients than in controls (645T carrier status frequency 0.45 versus 0.31, OR = 1.8, 95% CI 1.22.7, P = 0.005; 1953C frequency 0.45 versus 0.30, OR = 1.9, 95% CI 1.92.9, P = 0.001 and 2253A frequency 0.40 versus 0.28, OR = 1.7, 95% CI 1.12.6, P = 0.01). Among HIV cases, two SNPs in TLR9 that are in linkage disequilibrium [Gp1174A (untranslated) & A1635G (P545P)] were independently associated with faster CD4 decline. The A1635G SNP showed an additive effect on CD4 decline with a mean slope of -1.78 for A/A, -1.88 for A/G (P = 0.2) and -2.08 for G/G (P = 0.008). When we stratified HIV+ patients into progression groups, we observed that 1635G carriers were more frequent among rapid progressors than others (OR = 1.8, 95% CI 0.983.2, P = 0.058 for G/A versus A/A and 2.7, 95% CI 1.45.2, P = 0.003 for G/G versus A/A). Similar results were found for Gp1174A and when we calculated the slope with individual regression or latent variable.
This is the first demonstration of an association of TLR SNPs (TLR9) with the progression of HIV infection. In addition, we found a different distribution of 3 SNPs in TLR8 in HIV+ individuals and healthy blood donors. Genetic studies in other cohorts will help to further assess the role of these SNPs as prognostic markers of HIV infection. In vitro studies will allow to understand the functional role of TLRs and their mutations in HIV infection.
|Session name:||XXIst ISTH Congress|
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