Association of TLR7 Variants with AIDS-Like Disease and AIDS Vaccine Efficacy in Rhesus Macaques 英文参考文献.docVIP

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Association of TLR7 Variants with AIDS-Like Disease and AIDS Vaccine Efficacy in Rhesus Macaques 英文参考文献.doc

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Association of TLR7 Variants with AIDS-Like Disease and AIDS Vaccine Efficacy in Rhesus Macaques 英文参考文献

AssociationofTLR7VariantswithAIDS-LikeDiseaseand AIDSVaccineEfficacyinRhesusMacaques RomanA.Siddiqui1,2¤,MichaelKrawczak3,MatthiasPlatzer2,UlrikeSauermann1* 1GermanPrimateCenter,LeibnizInstituteforPrimateResearch,Go¨ttingen,Germany,2GenomeAnalysis,LeibnizInstituteforAgeResearch–FritzLipmannInstitute,Jena, Germany,3InstituteofMedicalInformaticsandStatistics,Christian–AlbrechtsUniversity,Kiel,Germany Abstract InHIVinfection,TLR7-triggeredIFN-aproductionexertsadirectantiviraleffectthroughtheinhibitionofviralreplication, butmayalsobeinvolvedinimmunepathogenesisleadingtoAIDS.TLR7couldalsobeanimportantmediatorofvaccine efficacy.Inthisstudy,weanalyzedpolymorphismsintheX-linkedTLR7geneintherhesusmacaquemodelofAIDS.Upon resequencing of the TLR7 gene in 36 rhesus macaques of Indian origin, 12 polymorphic sites were detected. Next, we identifiedthreetightlylinkedsinglenucleotidepolymorphisms(SNP)asbeingassociatedwithsurvivaltime.Genotypingof 119 untreated, simian immunodeficiency virus (SIV)-infected male rhesus macaques, including an ‘MHC adjusted’ subset, revealedthatthethreeTLR7SNPsarealsosignificantlyassociatedwithset-pointviralload.Surprisingly,thiseffectwasnot 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 17bp upstream of the ATG translationinitiationcodon,thatisalsopotentiallycapableofinfluencingRNAstructure.Inc.13Acarriers,neitherset-point viral load nor survival time were related to the c.-17C.T genotype. In c.13G carriers, by contrast, the c.-17C allele was significantlyassociatedwithprolongedsurvival.Again,nosuchassociationwasdetectedamongimmunizedSIV-infected macaques.OurresultshighlightthedualroleofTLR7inimmunodeficiencyvirusinfectionandvaccinationandimplythatit maybeimportanttocontrolhumanAIDS