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-kB-responsive. This is important because NF-kB is a key mediator of the inflammatory and innate immune responses. NF-kB stimulates the host response to stress by activating genes that promote cell growth and survival, and constitutive activation of NF-kB contributes to malignant development. We hypothesize that activation of NF-kB 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 the E6 and E7 viral proteins activate NF-kB in different cell types of the reproductive tract? 2) Does NF-kB activation in HPV-infected cervical cells enhance cell growth, survival, or 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-kB is a central regulator of the inflammatory and innate immune responses. Therefore, our results will provide basic information on how HPV might alter host response to infection.