title: A common polymorphism in TLR3 confers natural resistance to HIV-1 infection.
abstract: TLR3 recognizes dsRNA and activates antiviral immune responses through the production of inflammatory cytokines and type I IFNs. Genetic association studies have provided evidence concerning the role of a polymorphism in TLR3 (rs3775291, Leu412Phe) in viral infection susceptibility. We genotyped rs3775291 in a population of Spanish HIV-1-exposed seronegative (HESN) individuals who remain HIV seronegative despite repeated exposure through i.v. injection drug use (IDU-HESN individuals) as witnessed by their hepatitis C virus seropositivity. The frequency of individuals carrying at least one 412Phe allele was significantly higher in IDU-HESN individuals compared with that of a matched control sample (odds ratio for a dominant model = 1.87; 95% confidence interval, 1.06-3.34; p = 0.023). To replicate this finding, we analyzed a cohort of Italian, sexually HESN individuals. Similar results were obtained: the frequency of individuals carrying at least one 412Phe allele was significantly higher compared with that of a matched control sample (odds ratio, 1.79; 95% confidence interval, 1.05-3.08; p = 0.029). In vitro infection assays showed that in PBMCs carrying the 412Phe allele, HIV-1(Ba-L) replication was significantly reduced (p = 0.025) compared with that of Leu/Leu homozygous samples and was associated with a higher expression of factors suggestive of a state of immune activation (IL-6, CCL3, CD69). Similarly, stimulation of PBMCs with a TLR3 agonist indicated that the presence of the 412Phe allele results in a significantly increased expression of CD69 and higher production of proinflammatory cytokines including IL-6 and CCL3. The data of this study indicate that a common TLR3 allele confers immunologically mediated protection from HIV-1 and suggest the potential use of TLR3 triggering in HIV-1 immunotherapy.
authors.affiliation: Scientific Institute for Recovery and Care E. Medea, 23842 Bosisio Parini, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
authors.forename: Mara
authors.initials: M
authors.lastname: Biasin
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.forename: Diego
authors.initials: D
authors.lastname: Forni
authors.forename: Mariacristina
authors.initials: M
authors.lastname: De Luca
authors.forename: Irma
authors.initials: I
authors.lastname: Saulle
authors.forename: Sergio
authors.initials: S
authors.lastname: Lo Caputo
authors.forename: Francesco
authors.initials: F
authors.lastname: Mazzotta
authors.forename: Juan
authors.initials: J
authors.lastname: Macías
authors.forename: Juan A
authors.initials: JA
authors.lastname: Pineda
authors.forename: Antonio
authors.initials: A
authors.lastname: Caruz
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
mesh_terms: D002478:Cells, Cultured; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000276:immunology; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D018023:HIV Seronegativity / Q000235:genetics / Q000276:immunology; D006801:Humans; D007558:Italy; D007930:Leucine / Q000235:genetics; D008297:Male; D010649:Phenylalanine / Q000235:genetics; D011110:Polymorphism, Genetic / Q000276:immunology*; D011446:Prospective Studies; D013030:Spain; D051196:Toll-Like Receptor 3 / Q000235:genetics*
chemical_list: C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D010649:Phenylalanine; D007930:Leucine