The incidence of anal cancer is increasing among homosexual men, and may be linked to the AIDS epidemic. Based on San Francisco Bay Area SEER data, a more than seven-fold increase in the annual incidence of anal cancer in never-married men has occurred since 1973. Furthermore, based on our preliminary data and current survival statistics, we project that a minimum of 10% of men with a non-AIDS Group IV HIV diagnosis will develop anal cancer within their lifetime. The purpose of this proposal is to study the development and progression of precancerous cytologic and histopathologic changes of the anal epithelium among HIV-positive and HIV-negative homosexual men, and to identify risk factors associated with these processes. We will study 400 men with Group II HIV disease as they progress to Group IV HIV disease, and 200 HIV- negative homosexual men. Questionnaires will be administered detailing medical and smoking history, drug use, sexual habits and other potentially relevant information. One anal swab will be obtained for anal cytology, followed by another for HPV DNA hybridization studies. Anoscopy and biopsy of areas suggestive of disease will be performed. Immune status will be measured using CD4 counts and beta-2 microglobulin levels. All subjects will be prospectively followed every 6 months with an abbreviated questionnaire and repeat of the above laboratory tests. The status of HIV- negative subjects will be monitored at each visit using the polymerase chain reaction and an ELISA test for HIV antibodies. HPV DNA hybridization studies will be performed using Southern blot analysis and the polymerase chain reaction. All cytology slides and biopsies will be interpreted by two pathologists who have no knowledge of the HIV status of the subjects or the results of HPV DNA hybridization. Similar to cervical cancer, invasive anal cancer is a preventable disease. Knowledge of the natural history of precancerous changes and risk factors associated with progression is critical to identify patients at highest risk for anal cancer. Screening in high risk groups would follow from this knowledge, enabling early diagnosis and treatment of AIN before the development of invasive cancer. In addition, the relationship between anal neoplasia and HIV-associated immunosuppression is a paradigm for the relationship between HPV-associated neoplasia and immunosuppression in general. These studies may therefore provide valuable information relevant to other diseases as well, such as cancer of the cervix.