Core C Abstract: Long-acting nanoformulated antiretroviral therapy (nanoART) is poised for bench to bedside clinical translation. However, hurdles remain to see nanoART as a significant part of the therapeutic armamentarium. This includes, but is not limited to, evidence for improved dosing, tissue biodistribution and pharmacodynamics (PD). All require support from readily available and affordable rodent models of human immunodeficiency virus (HIV)-infection for PD and pharmacokinetic (PK) and antiretroviral efficacy tests as performed on non- human primates. To these ends, the Core C animal model core will provide humanized mice for efficacy evaluation and rhesus macaques for PK and tissue distribution testing and pilot efficacy studies. The purpose is to assist researchers with animal experiments (Projects 2 and 3 and Core B). These will include assessments of viral and immune parameters, tissue dissections and when relevant, biopsies of lymph nodes and rectal tissues. All will be processed, in collaborative experiments, for molecular, virologic and biochemical studies. The goal of the humanized mice component is to assess direct antiretroviral efficacy and HIV eradication experiments of selected and drug formulation combinations. Based on the program needs specific formulations will contain GSK744 and GSK8232, an integrase and maturation inhibitor, respectively, or mixtures of both. Alternatively, prodrugs of 3TC, abacavir, maraviroc, and ritonavir-boosted atazanavir will be used, in part, as combination therapy. These nanoformulations or their combinations will be tested for their abilities to reduce residual virus or eradicate HIV when administered with indoleamine 2, 3-dioxygenase inhibitors in platform development. Humanized mice will be employed for metabolomics and molecular imaging studies in order to provide rapid assessments of drug success or failures as they can assess tissue homeostasis and predict end organ disease. Non-human primates will be made available, specifically for drug PK, tissue distribution and toxicological studies. Tissue distribution will be assessed in bioimaging experiments (Project 3) by ligand-targeted magnetite nanoformulations and linked back to PK and PD tests as contained in Projects 1, 2 and Core B.
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