HUMAN PAPILLOMAVIRUS EARLY GENES AS A MECHANISM FOR INNATE IMMUNESYSTEM EVASION THROUGH THE CGAS-STING PATHWAY
PublisherThe University of Arizona.
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AbstractHuman Papillomavirus is the most common sexually transmitted infection in the UnitedStates and in the top three worldwide, infecting up to 80% of the population, and causing around5% of cancers including almost all cases of cervical cancer. Research in this field may seeminconsequential since there is a vaccination in place; however, in most of the world, this vaccineis unobtainable or unaffordable while HPV still infects a vast majority of the population, makingresearch in the field important to treatment and understanding of the virus.Previous work has found that HPV E6 and E7 oncogenes interfere with p53 and pRbfunction. E6 and E7 inhibition of p53 and pRb lead to uncontrolled cell growth which underliesHPV’s oncogenicity. The cGAS-STING pathway is an innate immune pathway that sensescytosolic DNA causing the phosphorylation and activation of STING and IRF3 to initiateantiviral interferon (IFN) responses. Our preliminary data suggest that HPV18-immortalizedkeratinocytes, which express physiological levels of HPV oncogenes, have a defectivecGAS-STING response.I hypothesize that E6 and/or E7 alone may inhibit cGAS-STING antiviral responses, inaddition to known roles in antagonizing p53 and pRb. To test this hypothesis, I attempted togenerate a panel of HaCaT keratinocytes that stably expressed PV oncogenes either alone or incombination. I also attempted retroviral vector transduction of HaCaTs to generate clonesexpressing E6 and/or E7. If my hypothesis is correct, there would be lower levels of pIRF3 andpSTING in some E6 and/or E7-expressing cells compared to controls. Understandingmechanisms of specific oncogene inhibition of cGAS-STING innate immune responses wouldadvance our understanding of how high-risk HPV may evade the innate immune system toestablish persistent infections, the risk factor for HPV-associated cancers.
Degree ProgramMolecular and Cellular Biology