Worldwide, invasive cervical cancer (ICC) is the second most common cancer among women, and is of particular importance in developing countries. It has become apparent that women throughout the world are increasingly at risk for infection with HIV-1 or HIV-2 (in West Africa); that most women acquiring HIV also are infected with HPV; and that co-infection with these two viruses increases risk for squamous cell neoplasia. Some have suggested that the increase in cervical intraepithelial neoplasia (CIN) among women with HIV is the result of HIV induced immunosuppression which permits prolonged and increased HPV expression resulting in a greater likelihood of CIN. Others suggest direct upregulation of HPV by HIV. However, there have not been any in vivo studies examining the molecular basis for the increased risk of neoplasia associated with HIV. We propose that the increased risk for CIN conferred by HIV is related to alterations of molecular events which have been shown to be important in the development of ICC. We hypothesize that ICC and CIN2-3 present in HIV infected women will differ from that in HIV seronegative women with respect to (i) the distribution of HPV-16 variants present, (ii) the stage in the development of cervical neoplasia at which telomerase is activated, and the levels of telomerase present, and (iii) the proportion of CIN2-3 in which genomic mutations are detected. The proposed study is a logical extension of our ongoing study in Senegal West Africa. Samples from women enrolled in our ongoing cohort study will be used in the proposed study. Additionally, we will recruit and biopsy women with cervical intraepithelial neoplasia grades 1-3, atypia (ASCUS) and invasive cancer. Learning more about interrelationships between HPV variants, telomerase and genetic mutations in the pathogenesis of cervical cancer should suggest new methods for identifying women (especially HIV infected women) at highest risk for cancer, should aid in development of new strategies to treat cervical neoplasia in women with HIV who have been shown to be resistant to conventional ablative therapy, and could have implications for prophylactic or therapeutic vaccine development.
