Anal intraepithelial neoplasia associated with human papillomavirus (HPV) disproportionately affects individuals who are infected with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS). HPV is the most common sexually transmitted infection worldwide. At least 75% of all sexually active individuals will be infected or diagnosed with one of the many HPV strains in their sexual lifetime. Oncogenic HPV is a particularly opportunistic infection amongst the HIV-positive population, with a near universal presence in the HIV-positive men who have sex with men. It is estimated in 2011, HPV is responsible for 5200 new cases of anal cancer and 720 deaths in both men and women in the United States. The incidence of anal cancer is increasing among several subgroups, in particular men who have sex with men and people with HIV/AIDS. HIV-infected incidences of anal intraepithelial neoplasia (AIN) are 10-50 times greater in MSM when compared with the general population. The widespread availability of highly active antiretroviral therapy beginning in 1996 dramatically decreased mortality rate of HIV-positive individuals. Despite overall improved survival, HIV-positive individuals remain at an increased risk for anal cancer because of prolonged HIV-induced immune suppression. Therefore, the specific aims of this study are to identity preventative interventions by using high-throughput screening to (1) identify novel compound(s) that inhibit HPV pseudovirions from entering epithelial cells with an acceptable toxicity profile and (2) determine the mechanism(s) by which the novel compounds identified in Aim 1 inactivate pseudovirions or inhibit entry of pseudovirions or into epithelial cells.
Results from this study have the potential to identify the mechanism(s) of a novel compound able to inactivate or inhibit HPV from entering epithelial cells. The identification of molecular mechanisms will help us develop modalities that could prevent HPV infection and anal intraepithelial neoplasia (AIN) among HIV-positive individuals thereby addressing an area of great clinical need. As the literature on this area of research is limited, the knowledge obtained from this research training proposal has the potential to contribute to the development and testing of prophylactic interventions. These interventions will help prevent HPV infection and AIN in the HIV-positive and non HIV-positive individuals. According to The National Cancer Institute the rate of AIN resulting from oncogenic HPV in the HIV-positive population increased three-fold from 1991 to 2005. An investigation into novel compound(s) that will act as potent inhibitors of HPV infection and HPV-related neoplasia will provide new knowledge in developing interventions to prevent repeated exposure of oncogenic HPV. The burden of HPV AIN falls disproportionately among the HIV-positive individuals. This burden of AIN and anal cancer related to HPV infection has effectively identified the HIV-positive population as an area of emerging clinical and public health need.