association of tlr7 variants with aids-like disease and aids vaccine efficacy in rhesus macaques协会tlr7变异与疑似艾滋病疾病和艾滋病疫苗功效在恒河猴.pdfVIP

Association of TLR7 Variants with AIDS-Like Disease and AIDS Vaccine Efficacy in Rhesus Macaques 1,2¤ 3 2 1 Roman A. Siddiqui , Michael Krawczak , Matthias Platzer , Ulrike Sauermann * ¨ 1 German Primate Center, Leibniz Institute for Primate Research, Gottingen, Germany, 2 Genome Analysis, Leibniz Institute for Age Research–Fritz Lipmann Institute, Jena, Germany, 3 Institute of Medical Informatics and Statistics, Christian–Albrechts University, Kiel, Germany Abstract In HIV infection, TLR7-triggered IFN-a production exerts a direct antiviral effect through the inhibition of viral replication, but may also be involved in immune pathogenesis leading to AIDS. TLR7 could also be an important mediator of vaccine efficacy. In this study, we analyzed polymorphisms in the X-linked TLR7 gene in the rhesus macaque model of AIDS. Upon resequencing of the TLR7 gene in 36 rhesus macaques of Indian origin, 12 polymorphic sites were detected. Next, we identified three tightly linked single nucleotide polymorphisms (SNP) as being associated with survival time. Genotyping of 119 untreated, simian immunodeficiency virus (SIV)-infected male rhesus macaques, including an ‘MHC adjusted’ subset, revealed that the three TLR7 SNPs are also significantly associated with set-point viral load. Surprisingly, this effect was not observed in 72 immunized SIV-infected male monkeys. We hypothesize (i) that SNP c.13G.A in the leader peptide is causative for the observed genotype-phenotype association and that (ii) the underlying mechanism is related to RNA secondary structure formation. Therefore, we investigated a fourth SNP (c.-17C.T), located 17 bp upstream