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| |  Course of HIV Infection Influenced by Toll-like Receptors: Presented at ECCMID By Chris Berrie NICE, FRANCE -- April 7, 2006 -- A role has been confirmed for Toll-like receptors (TLRs) in the pathogenesis of HIV infection, with implications for disease progression and infectivity as well, according to a study presented here at the 16th European Congress of Clinical Microbiology and Infectious Diseases. TLR membrane proteins are known to be essential for their innate immune recognition of pathogens. Since single nucleotide polymorphisms (SNPs) of TLRs are associated with increased or decreased susceptibility to infections, Pierre-Yves Bochud, MD, principal investigator and post doctoral student, Institute for Systems Biology, Seattle, United States, and colleagues conducted a study to determine whether SNPs on TLR2, 3, 4, 7, 8 and 9 are associated with susceptibility to HIV-1 infection and its clinical course. "Susceptibility to HIV infection and time to AIDS are very variable among individuals," noted Dr. Bochud, MD, who presented the analysis of single nucleotide polymorphisms (SNPs) in HIV-positive patients. "It is known that genetic variations in the host are associated, at least in part, with such inter-individual differences." Dr. Bochud's team genotyped 1255 HIV-positive patients (1055 Caucasian) and 128 healthy blood donors for controls living in Switzerland. Access to known SNP databases allowed the selection of 28 SNPs. Individual viral loads were determined from the mean log HIV ribonucleic acid (RNA) copies/mm3 blood within 18 months of starting on highly-active antiretroviral therapy (HAART). For the evaluation of individual CD4 decline, linear regression of subjects' CD4 measures were used to define "individual CD4 slopes" in 435 Caucasian individuals who had had a sufficient number of CD4 measurements taken before participating in HAART. These individual CD4 slopes provided a measure of progression of disease, where "rapid progressors" showed slopes below the 15th percentile. This measurement identified which patients were immunocompromised rapid progressors who would likely proceed to full-blown AIDS within 5 years. This measurement also provided the necessary link to the genetic analysis of these individuals. The two SNPs in TLR9 that were found to be associated with rapid progression were in linkage disequilibrium, and analysis of the TLR9 1635 A/G SNP in a likelihood ratio test showed a highly significant P value even after adjustment (P =.007). A further search for correlation of the other SNPs did not reveal any associations with "slow progressors." For TLR8, Dr. Bochud said, "three polymorphisms in TLR8 were more frequent in the HIV patients than in the healthy blood donors." These were also in linkage disequilibrium, and after adjustment, only TLR8 1953 G/C remained significant (P =.02). Dr. Bochud indicated that none of the SNPs examined showed any association with viral load, and TLRs 2, 3, 4 and 7 showed no associations. He noted that the significant SNPs in TLR8 and TLR9 do not induce amino-acid changes in the protein products, and thus the mechanism could relate to different patterns of gene expression or splicing. He concluded by suggesting that "further studies are now needed to better understand the precise mechanisms of interaction between these TLRs and HIV-1."
[Presentation title: Polymorphisms in Toll-like Receptors Influence Susceptibility to and Clinical Course of HIV Infection. Abstract O396]
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