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The life cycle of human papillomavirus type 16 E6 variants and its effects on the innate immune system of host keratinocytes

dc.contributor.advisorZehbe, Ingeborg
dc.contributor.authorJackson, Robert
dc.description.abstractPersistent infection with human papillomavirus type 16 (HPV16) is the primary aetiological agent for cervical cancer. Viral particles initiate their life cycle by infecting basal keratinocytes of epithelium and amplifying their genome. Viral oncoproteins E6 and E7 are responsible for causing host cells to proliferate, disrupting the regular differentiation regimen. Infections are typically cleared by a host immune response, but HPV16 is capable of persisting, increasing the chance of genomic integration and host cell transformation. It is thought that HPV16 can evade the innate immune response by down-regulating important molecules such as toll-like-receptors (TLRs): normally responsible for recognizing viral infection and activating immune-response genes by a signal transduction cascade. Epidemiological studies show natural E6 variants, Asian-American (AA) and L83V, are found more often than the prototype in invasive cervical cancers. Increased oncogenic potential for AA and L83V E6 genes has been confirmed by recent studies, but the role of the viral life cycle remains uncertain for each variant. The effects of an active viral life cycle on innate immunity were tested by first establishing an organotypic tissue culture model for mimicking HPV-infected epithelium. This model was phenotypically verified by morphology and immunohistochemistry for HPV16 L2 capsid protein, proliferation marker BrdU, and differentiation markers K5 and K10. Expression analysis for viral and innate immune genes was performed using RT-qPCR. Significantly, TLR3 and IFN-κ were down-regulated in AA and L83V variants compared to prototype HPV16, indicating a variant-specific viral life cycle effect on host innate immune defence. Future high-throughput analyses, such as microarray or RNA-sequencing, can be used for global expression profiling.en_US
dc.subjectHuman papillomavirusen_US
dc.subjectHost keratinocytesen_US
dc.subjectHost cellsen_US
dc.subjectHost immune responseen_US
dc.subjectHost cell transformationen_US
dc.titleThe life cycle of human papillomavirus type 16 E6 variants and its effects on the innate immune system of host keratinocytesen_US
dc.typeThesisen_US of Scienceen_US Universityen_US
dc.contributor.committeememberMalek, Ladislav
dc.contributor.committeememberQin, Wensheng

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