Research Project
6493470
DESCRIPTION (provided by applicant): Laryngeal papillomatosis is a Human Papillomavirus (HPV) mediated disease characterized by multiple recurrences and frequent surgeries to maintain an airway. We have found that these infected cells have an impaired ability to present antigen to circulating CD8 T cells. TAP-1 (the Transporter Associated with Antigen Presentation) appeared to be reduced in laryngeal papillomatosis (HPV type 6111). Intriguing new results have lead us to postulate that this key transporter responsible for antigen presentation may not be lacking, but rather, because of an interaction with the E7 viral protein, TAP-1 is unavailable. This interaction imparts a functional consequence: purified HPV 11 E7 protein inhibited ATP-dependent peptide transport in vitro. The TAP-1 E7 interaction observed in HPV 11 seems to occur with HPV 16 as well, according to preliminary immunoprecipitation data, which has lead us to our hypothesis: we hypothesize that one of the conserved domains of E7 interact with TAP-1 and functionally disables it. This application has three specific aims to test the hypothesis: 1. To determine the critical region of HPV 11 E7 necessary for a physical interaction with TAP-1 and analyze whether this critical region also imparts functional inhibition of the transporter. 2. To determine if polymorphisms of TAP-1 or E7 can partially account for variations in disease susceptibility. 3. To determine whether the interaction between TAP-1 and E7 in naturally occurring infections sufficient to result in a loss of peptide transport and whether this loss correlates with viral protein load and the patients clinical course.
