title: TLR activation pathways in HIV-1-exposed seronegative individuals.
abstract: TLRs trigger innate immunity that recognizes conserved motifs of invading pathogens, resulting in cellular activation and release of inflammatory factors. The influence of TLR activation on resistance to HIV-1 infection has not been investigated in HIV-1 exposed seronegative (ESN) individuals. PBMCs isolated from heterosexually ESN individuals were stimulated with agonists specific for TLR3 (poly I:C), TLR4 (LPS), TLR7 (imiquimod), and TLR7/8 (ssRNA40). We evaluated expression of factors involved in TLR signaling cascades, production of downstream effector immune mediators, and TLR-expression in CD4+ and CD14+ cells. Results were compared with those obtained in healthy controls (HCs). ESN individuals showed: 1) comparable percentages of CD14+/TLR4+ and CD4+/TLR8+ CD14+/TLR8+ cells; 2) higher responsiveness to poly I:C, LPS, imiquimod, and ssRNA40 stimulation, associated with significantly increased production of IL-1beta, IL-6, TNF-alpha, and CCL3; 3) augmented expression of mRNA specific for other targets (CCL2, CSF3, CSF2, IL-1alpha, IL-8, IL-10, IL-12, cyclooxygenase 2) demonstrated by broader TLRs pathway expression analyses; and 4) increased MyD88/MyD88s(short) ratio, mainly following TLR7/8 stimulation. We also compared TLR-agonist-stimulated cytokine/chemokine production in CD14+ PBMCs and observed decreased IFN-beta production in ESN individuals compared with HCs upon TLR7/8-agonist stimulation. These data suggest that TLR stimulation in ESN individuals results in a more robust release of immunologic factors that can influence the induction of stronger adaptive antiviral immune responses and might represent a virus-exposure-induced innate immune protective phenotype against HIV-1.
authors.affiliation: Cattedra di Immunologia, Università degli Studi di Milano, Milan, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Biasin
authors.forename: Luca
authors.initials: L
authors.lastname: Piacentini
authors.forename: Sergio
authors.initials: S
authors.lastname: Lo Caputo
authors.forename: Valentina
authors.initials: V
authors.lastname: Naddeo
authors.forename: Piera
authors.initials: P
authors.lastname: Pierotti
authors.forename: Manuela
authors.initials: M
authors.lastname: Borelli
authors.forename: Daria
authors.initials: D
authors.lastname: Trabattoni
authors.forename: Francesco
authors.initials: F
authors.lastname: Mazzotta
authors.forename: Gene M
authors.initials: GM
authors.lastname: Shearer
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000634:Aminoquinolines / Q000276:immunology; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D015658:HIV Infections / Q000097:blood / Q000276:immunology* / Q000821:virology; D018023:HIV Seronegativity / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D000077271:Imiquimod; D007113:Immunity, Innate / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D011070:Poly I-C / Q000276:immunology; D012333:RNA, Messenger / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; C515429:CCL3 protein, human; D054405:Chemokine CCL3; D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C495344:TLR3 protein, human; C495345:TLR4 protein, human; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D011070:Poly I-C; D000077271:Imiquimod