Project Summary/Abstract Novel targeted therapies for HPV-associated Non-AIDS-defining cancers (Biospecimens/Biocohort) The incidents of non-AIDS-defining cancers (NADC) are increasing in HIV-infected individuals (HIVIIs), urging the development of therapeutic interventions. Many HIV-associated cancers are a result of co-infections with oncogenic viruses, and the high-risk human papillomavirus (HPV) is prevalent in the development of several NADCs, including head-and-neck (HNC) and anal cancers. Importantly, the HPV viral oncogenes are involved in the transformation and maintenance of these cancers and are considered unique targets in HPV-associated malignancies. Often considered `undruggable', these viral genes are susceptible to targeted gene therapeutic strategies and we have developed a novel, potent zinc finger protein (ZFP) that can strongly repress viral oncogenes to elicit anti-cancer effects; a promising approach to HPV-associated NADCs. Furthermore, lipid nanoparticles (LNPs) are a therapeutically relevant non-viral delivery system, which we have used previously for in vivo delivery of RNA-based therapeutics. Importantly, even though the HPV oncogenes represent viable therapeutic targets, there are no studies investigating the potential anti-proliferative effect of targeting the viral oncogenes in HPV-associated tumors from HIVIIs in vivo. Our long-term goal is to develop innovative interventions for the treatment of virally driven cancers emerging in HIVIIs, with the objective of this project to use LNP-delivered ZFP repressors to inactive HPV oncogenes in NADCs. Guided by our strong preliminary data and expertise using targeted repressors and nanoparticle delivery systems, we propose two complementary but distinct objectives, 1) the characterization of novel, potent ZFP repressors for anti-proliferative effects in HPV- associated cell line models relevant to NADCs, and 2) to assess LNP-delivered anti-HPV effectors to inhibit HPV-associated HNCs from HIVIIs in a patient-derived xenograft (PDX) murine model. Collectively, this work will be impactful by developing an innovative targeted repressor to inhibit HPV-associated NADCs, offering a novel intervention to malignancies increasing in HIVIIs.