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A common polymorphism in TLR3 confers natural resistance to HIV-1 infection.
Sironi, Manuela; Biasin, Mara; Cagliani, Rachele; Forni, Diego; De Luca, Mariacristina; Saulle, Irma; Lo Caputo, Sergio; Mazzotta, Francesco; Macías, Juan; Pineda, Juan A; Caruz, Antonio; Clerici, Mario.
Afiliação
  • Sironi M; Scientific Institute for Recovery and Care E. Medea, 23842 Bosisio Parini, Italy.
J Immunol ; 188(2): 818-23, 2012 Jan 15.
Article em En | MEDLINE | ID: mdl-22174453
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Polimorfismo Genético / Infecções por HIV / Predisposição Genética para Doença / Receptor 3 Toll-Like Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Limite: Humans / Male País como assunto: Europa Idioma: En Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Polimorfismo Genético / Infecções por HIV / Predisposição Genética para Doença / Receptor 3 Toll-Like Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Limite: Humans / Male País como assunto: Europa Idioma: En Ano de publicação: 2012 Tipo de documento: Article