title: Expression of nucleic acid-sensing Toll-like receptors predicts HPV16 clearance associated with an E6-directed cell-mediated response.
abstract: Toll-like receptors (TLRs), important in rapid clearance of incident human papillomavirus (HPV) infections, may also be important in shaping the adaptive response to persistent infections. We examined here the association between TLR expression and clearance of HPV16 infections following periods of persistence, using longitudinal TLR measurements and a time-to-clearance analysis, as well as the interaction between TLRs and adaptive, cell-mediated responses involved in clearance. TLR2, TLR3, TLR7, TLR8 and TLR9 mRNA expression were measured in cervical cytobrush samples by quantitative PCR. Responses to the HPV16 E6 and E7 oncoproteins were measured by an interferon-γ immunospot assay. Bivariable and multivariable Cox proportional hazard models were used to estimate the effect of TLRs on HPV16 clearance. Higher expression of TLR3 or TLR7 at an HPV16-positive visit was a significant (p ≤ 0.05) predictor of clearance by the following visit, in both unadjusted and adjusted (for smoking and oral contraceptive use) models. In women with, but not those without, a positive response to E6, higher expression of TLR3 (hazard ratio: 1.2 [95% confidence interval: 1.04-1.39], p = 0.012), TLR7 (1.39 [1.14-1.7], p = 0.001), TLR8 (1.37 [1.11-1.69], p = 0.003), or TLR9 (1.53 [1.13-2.08], p = 0.006) was significantly associated with clearance, revealing an important link between innate and adaptive immunity in the control of HPV infections following periods of persistence.
authors.affiliation: Department of Pediatrics, Division of Adolescent Medicine, School of Medicine, University of California, San Francisco, CA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Scott
authors.forename: Yifei
authors.initials: Y
authors.lastname: Ma
authors.forename: Sepideh
authors.initials: S
authors.lastname: Farhat
authors.forename: Anna-Barbara
authors.initials: AB
authors.lastname: Moscicki
mesh_terms: D056704:Adaptive Immunity; D000293:Adolescent; D005260:Female; D052162:Human papillomavirus 16 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D008137:Longitudinal Studies; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins / Q000378:metabolism; D030361:Papillomavirus Infections / Q000235:genetics* / Q000276:immunology* / Q000821:virology; D016016:Proportional Hazards Models; D012097:Repressor Proteins / Q000378:metabolism*; D013997:Time Factors; D051193:Toll-Like Receptors / Q000235:genetics*; D014626:Vaginal Smears; D055815:Young Adult
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D051193:Toll-Like Receptors; C059731:oncogene protein E7, Human papillomavirus type 16
keywords: Toll-like receptors; cell-mediated immunity; cohort study; human papillomavirus infection; women