The incidence of anal cancer, which is largely caused by sexually transmitted human papillomaviruses (HPVs), has been increasing for many years, especially in people living with human immunodeficiency viruses (HIV+). The Department of Veterans Affairs cares for the largest population of people living with human immunodeficiency virus of any healthcare system in the nation. One opportunity for preventing this deadly cancer lies in the effective treatment of precancerous anal intraepithelial neoplasia (hereafter referred to as anal dysplasia). Unfortunately, current treatments for anal dysplasia are ineffective, with high recurrence rates and unwanted, long-term side effects. Dr. Carchman’s laboratory studies anal carcinogenesis in a well- validated, HPV-transgenic model. Through collaborations Dr. Carchman also has access to a new conditional transgenic mouse model to study anal carcinogenesis to facilitate mechanistic studies and test therapeutic agents. Dr. Carchman has identified autophagic dysfunction due to HPV16 E6 and E7 expression that results in anal cancer development. Dr. Sherer’s laboratory has determined that HIV-1 protease inhibitors result in the degradation of HPV E6 and E7, which prevent the destruction of p53, a potent inducer of autophagy. These findings have led the team to pursue preclinical studies that re-purpose HIV protease inhibitors—previously an integral part of HIV treatment—in a topical form to treat anal dysplasia and prevent cancer development. While protease inhibitors have been shown to induce autophagy in several preclinical and clinical studies, they have not been examined in anal dysplasia treatment. The overall hypothesis is that autophagic induction with topical protease inhibitors will prevent the progression of anal dysplasia in preclinical models of anal carcinogenesis, thus providing an effective therapeutic option to prevent HPV-associated anal cancer in humans. The goal of this proposal is to utilize novel preclinical models of HIV-associated anal carcinogenesis, which include a single-cell culture where E6 and E7 are green fluorescent protein (GFP) tagged, an established HPV-transgenic model, and a conditional HPV transgenic model that will undergo immune modulation to recapitulate HIV infection. The team is uniquely positioned to carry out this proposed study. Dr. Carchman has clinical expertise in anal dysplasia and anal cancer and is the leader of the anal dysplasia/cancer clinic at the University of Wisconsin-Madison. The group also has extensive expertise with preclinical models for anal carcinogenesis. These models recently yielded the key observation that autophagy is important for inhibiting anal carcinogenesis—a discovery that drives the proposal’s central premise that HIV protease inhibitors, known to induce autophagy, can be re-purposed as topical agents to prevent anal cancer. The team’s work brings a cancer-relevant problem in the context of an HIV infection back into focus. This research ...