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Transcript
Immunology of HPV Infection Craig Woodworth Department of Biology Clarkson University Potsdam, NY The Natural History of HPV Infection Suggests that Immunity is Effective • Most HPV infections are cleared without clinical disease. When lesions develop, they regress after several months • Individuals who have decreased cell mediated immunity (transplant recipients and patients with HIV) have an increased prevalence and persistence of HPV infections • The humoral immune response accompanies papilloma regression, and is effective in preventing reinfection • Immunity to HPV is effective but often delayed The Papillomavirus Life Cycle has Evolved to Evade the Immune Response capsid assembly and virus release expression of late genes E6/E7 expression DNA replication low level episomal replication persistence of HPV and malignant progression The Innate Immune System is the First Line of Defense Against HPV epithelial barrier type I interferons toll-like receptors HPV-infected keratinocytes macrophages proinflammatory cytokines NK cells Type I Interferons Exert Direct Antiviral Effects • Interferons a and b are produced by HPV-infected keratinocytes • Inhibit cell proliferation and immortalization of HPVexpressing keratinocytes • Down regulate expression of the HPV-16 E6 and E7 proteins in immortal keratinocytes • Stimulate expression of HLA class I proteins • However, therapy using type I interferons has had variable success…. HPV-16 E6 and E7 Proteins Directly Inhibit Interferon Signaling IFN interferon a R2 interferon a R1 TYK2 E6 STAT2 STAT1 cytoplasm nucleus ISGF3 E7 p48 ISRE E6 E7 inhibits IRF-3 and IRF-1 Inflammation is Important for Innate and Adaptive Immunity IL1 cell lysis & release of bioactive IL1-a IL18 TLRs TNF NF-kB cytokines (IL1, TNF-a) IL-12, IFN-g, chemokines, & ‘danger’ signals Imiquimod Activates the Toll-Like Receptor 7 imiquimod TLR-7 cell lysis & release of bioactive IL1-a NF-kB cytokines (IL1, TNF-a) IL-12, IFN-g, chemokines, & ‘danger’ signals HPV-16 E6 and E7 Proteins Interfere with Proinflammatory Signaling E6/E7 IL1 cell lysis & release of bioactive IL1-a E6 E6 TLRs TNF NF-kB cytokines (IL1, TNF-a) IL-12, IFN-g, chemokines, & ‘danger’ signals HLA Class I and II Proteins • HLA class I proteins are expressed on the surface of keratinocytes and contribute to immune recognition • HLA class II proteins are expressed by Langerhans cells and are required for cross presentation of antigens • Specific HLA haplotypes are associated with protection from cervical cancer (HLA DRBI * 13 / DBQI * 0603) • Cervical cancers show down regulation of HLA class I and up regulation of class II proteins HPV Early Proteins Alter Expression of MHC Class I Genes E5/E7 TAP-1 HPV antigens E5 proteasome class I HLA E5/E7 HLA class I transcription ER NK Cells and Macrophages • NK cells target HPV-infected keratinocytes that express low levels of class I protein • HPV-infected keratinocytes are relatively resistant to NK mediated lysis, but sensitive to LAK cells • NK activity is decreased in patients with precancerous or malignant anogenital disease • Macrophages are present in regressing papillomas, they produce 1L-12, and they contribute to elimination of HPV-infected cells • Dysregulation of MCP-1 gene expression and lack of macrophage infiltration may contribute to HPVlinked carcinogenesis Adaptive Immune Response to HPV activated macrophages Th1 helper T cells secretion of IgG memory T cells HPV-infected keratinocytes stimulation of a Th1 type cell mediated immune response Langerhans cells mature and migrate to lymph nodes where they cross present HPV antigens Langerhans Cells Cross Present HPV Antigens to the Immune System HPV antigens + ‘danger signal’ IL-10 TGF-b1 HPV-infected keratinocyte Langerhans cell lymphocyte A Th1 Helper T Cell Response is Associated with Papilloma Regression Th1 helper T cell response regressing HPV infections IFN-g, IL-2, TNF-a IL-12 IFN-g Th1 Th2 helper T cell response progressing HPV infections IL-4, IL-5, IL-10 IL-4 TGF-b Th2 Immune Events in Regressing Papillomas • Non-regressing papillomas contain few immune cells and no inflammation • Regression is associated with a Th1 type cell mediated immune response and increased expression of IFN-g, IL-12, and TNF-a • There is a large infiltration of mononuclear cells in the epithelium and stroma. This consists of CD4+ cells, macrophages, and CD8+ cells • Infected keratinocytes express HLA class II proteins and ICAM-1 The Humoral Immune Response Protects Against Reinfection • An antibody response to the L1 protein occurs commonly after HPV infection. Seroconversion is delayed for several months • Both IgG and IgA are secreted. The IgG response to the L1 capsid protein is type-specific and longlasting (over 10 years). The IgA response may be as long lived • Antibodies are neutralizing and are directed to conformational epitopes on L1. • The humoral immune response protects against reinfection, but does not cause regression of existing papillomas Summary • Most HPV infections are not apparent or regress, suggesting that the host’s immune response is effective • The HPV life cycle has evolved to evade the host’s immune response, and HPV early proteins directly inhibit specific components of immunity • Papilloma regression is mediated by a Th1 type cell mediated immune response with infiltration of macrophages and CD4+ cells • Humoral immunity is protective and is mediated by neutralizing antibodies to conformation specific epitopes of the L1 protein Questions • How do HPV-16 early genes alter the ability of infected keratinocytes to contribute to the innate and adaptive immune responses? • What is the most effective method for preventing tolerance or stimulating a strong Th1 helper T cell response? • Do the innate and adaptive immune responses differ in the cervical transformation zone where most carcinomas develop?