HUMAN PAPILLOMAVIRUS SPECIFIC T-CELL RESPONSES

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Our long-term goal is to identify Human Papillomavirus (HPV) synthetic peptides that have potential as immunotherapeutic and/or vaccine reagents against HPV-associated cervical neoplasia. We and others have shown that HPV is associated with the majority of preinvasive and invasive carcinomas (CIN) of the uterine cervix and has been found to contribute in a significant way to the genesis of human genital cancer. Curiously, some HPV infected patients develop cervical neoplasms while others do not. Also, patients with defects in cell mediated immunity have an increased prevalence of HPV-associated diseases. It is, therefore, important to understand cell mediated immune responses (both helper T- and cytotoxic T- cell immunity) in order to develop strategies for efficient immunoprevention and immunotherapy of HPV-positive tumors. We propose to determine HPV-specific T cell responses in women with HPV-associated CIN and compare their levels with those in women with no signs of HPV infection and/or CIN. We will also compare these T cell responses to those in women that have undergone treatment and remained in a disease- free condition or with recurrent or persistent disease. This will be accomplished by: (a) preparing synthetic peptides derived from HPV encoded E6/E7 oncoproteins and using them along with recombinant E6 and E7 proteins in T-cell proliferation studies on patient white blood cells, (b) determining whether these peptides sensitize HLA-matched target cells for lysis by cytotoxic T lymphocytes (CTLs) from patients, and (c) performing two-color immunofluorescence analysis of blood and tissue biopsy samples for HPV-specific T4- and T8-cells. While the major focus will be peptides from E6 and E7, the HPV proteins most commonly expressed in tumors, we will also search the literature for additional peptides from other HPV proteins. Positive results from these studies would identify HPV peptides that are tumor-specific T-cell antigens. These studies will provide the basis for future immunotherapeutic intervention in patients at risk for cervical cancer.