): Human papillomavirus (HPV) represents a unique tumor antigen system to determine whether a cell-mediated immune response can directly alter the development of cancer. DNA from human papillomaviruses (HPV) can be found in most cervical carcinomas, and the HPV E6 and E7 gene products are implicated in cervical carcinogenesis through their interaction with p53 and Rb. An intact cell-mediated immune system is thought to be critical for control of HPV infection, since 1) the vast majority of infected HPV+ patients will spontaneously clear their infection, 2 ) the development of cervical neoplasia is HLA-linked, and 3)immunodeficiency, such as HIV infection, alters the progression of HPV infection. There are several ongoing clinical trials [involving] vaccination with HPV E6 and E7-derived antigens, but many questions regarding the endogenous iLnmune response to remain to be addressed. Hypothesis: Infection of patients with human papillomavirus (HPV) subtype 16 triggers a measurable endogenous CD8+ cytotoxic T lymphocyte (CTL) response to HPV-derived peptides, and the failure to develop functional anti-HPV CTL correlates with persistence of infection and progression to cervical neoplasia. To address this hypothesis, Dr. Anderson plans to accomplish the following aims: 1) Using a combination of tetramer and ELISpot assays, determine whether normal HLA-A2+ blood donors have measurable and functional HPV16 E6 and E7-specific CTL, and whether these CTL can be expanded in vitro. 2) Determine if HPV16-infected patients mount an anti-HPV CTL response that inversely correlates with progression of cervical neoplasia. This will be done by enumerating, expanding, and phenotyping CTL from HPV16+ patients who have a range of cervical abnormalities, from normal cytology to cervical carcinoma. Dr. Anderson's research will be performed in a laboratory at the Dana-Farber Cancer Institute under the sponsorship of Dr. Lee M, Nadler, a leader in the f i eld of tumor immunology and experienced mentor of many successful physician/scientists.
