Cervical Cancer remains one of the most common and morbid cancers among women living in sub- Saharan Africa, and the incidence of invasive cervical cancer (ICC) is nearly fivefold higher in women living with HIV (WLWH) compared to women living without HIV infection. ICC also disproportionately impacts medically marginalized women in the United States. ICC is a consequence of infection with a “high-risk” (hr) strain of human papillomavirus (HPV). There is an ordered progression from a healthy cervix to a cervix that is asymptomatically infected with hrHPV to low grade cervical dysplasia to high grade cervical dysplasia and eventually to ICC. The biologic determinants of this ordered progression have not been entirely established. Of note, a small proportion of women with cervical dysplasia will spontaneously regress their dysplastic lesions and sometimes clear hrHPV infection, and this appears to occur less frequently among WLWH. Primary prevention includes vaccines against HPV which are extremely effective, but nearly 4 in 5 women across the world have not been vaccinated against HPV. In women infected with hrHPV, secondary prevention includes treatment of high-grade dysplastic lesions. In resource limited settings, especially in areas with high levels of HIV, both screening for and eradication of dysplastic lesions remains challenging. Screening programs are often overwhelmed and rely on screening tests with limited accuracy and treatment regimens that have limited efficacy and some long-term morbidity. Our research team from has generated considerable preliminary data to understand the biologic determinants of progression and regression of cervical dysplasia among Ugandan women with and without HIV infection. This work has identified key biologic pathways that may be implicated in the regression of high-grade cervical dysplasia (CIN2/3), including those related to toll-like receptor pathways. We propose to further characterize the microenvironment of dysplastic cervical tissue and ICC in three cohorts, including of WLWH from Uganda, as well a cancer disparity study of African American women from East Cleveland, and to determine whether in an experimental model of HPV-associated cancer a vaginal application of novel formulations of TLR 7/8 agonist activates specific pathways and whether these pathways are associated with clinical regression of HPV-associated tumors. This work would both further the understanding of the role of the innate immune system in the tumor microenvironment of patients with HIV- associated malignancies and offer potential therapeutic strategies to a diverse group of patients with HIV and cancer.