Activation of NF-kB by Human Papillomaviruses

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DESCRIPTION (provided by applicant): Infection with a subset of human papillomaviruses (HPV) is the major risk factor for cervical cancer. The HPV E6 and E7 viral genes are selectively retained and expressed in most cervical cancer cells where they activate DNA synthesis and interfere with multiple regulatory pathways. We have found that expression of HPV-16 E6 and E7 genes in epithelial cells cultured from human cervix activates the transcription factor NF-kB and stimulates expression of multiple genes known to be NF-kappaB-responsive. This is important because NF-kB is a key mediator of the inflammatory and innate immune responses. NF-kappaB stimulates the host response to stress by activating genes that promote cell growth and survival, and constitutive activation of NF-kappaB contributes to malignant development. We hypothesize that activation of NF-kappaB provides cervical epithelial cells with a selective survival advantage and represents an important step in immortalization by HPV. The proposed work will address 2 related questions: 1) How do specific HPV genes activate NF-kB in human cervical epithelial cells? 2) Does NF-kappaB activation in HPV-infected cervical cells enhance immortalization by HPV? Epithelial cells will be cultured from the cervical transformation zone, where most cancers originate, and transfected with high risk, moderate risk, or low risk HPV genomes, or specific HPV- 16 genes. NF-kappaB activation will be determined using a reporter gene assay. Cervical cells will also be co-transfected with HPV-16 E6/E7 plus dominant negative NF-kB mutants or wild type p65 to examine whether alterations in NF-kappaB activation influence immortalization. Our results will clarify whether NF-kB is a potential target for therapy of HPV infection or cervical dysplasia. Epithelial cells contribute to innate immunity in the reproductive tract, and NF-kappaB is a central regulator of the inflammatory and innate immune responses. Therefore, our results will also provide basic information on how HPV might alter host response to infection.