Targeting Viral Reservoirs through PET-Informed Dosing of Curative Agents
Development of robust and validated methods to quantify tissue-specific drug exposure and the size of the HIV reservoir remains a critical challenge to inform strategies towards HIV cure. This proposal leverages three positron emission tomography-magnetic resonance (PET-MR) imaging clinical studies of radiolabeled raltegravir (RAL), broadly neutralizing antibody VRC01, and a non-specific marker of T cell activation (F-AraG) that allow us to visualize:
a) whole-body RAL pharmacokinetics (PK) and tissue distribution of RAL, b) whole-body distribution of latently infected cells and VRC01 PK, and, c) whole-body T cell activation (F-AraG) in people with HIV (PWH). Given the large amount of data produced by PET studies, simultaneous analysis of individual tissues temporally requires computational systems modeling approaches, that have not been performed in studies of HIV reservoirs. Utilizing data from the three clinical PET-MR studies and the complementary expertise of our team in HIV cure, clinical pharmacology, and pharmacometric modeling, we will establish physiological-based models of tissue-level distribution kinetics for RAL, VRC01 (as both a HIV tracer and therapeutic bnAb), and F-AraG to evaluate exposure of therapeutic dosing regimens of RAL and VRC01 (Aim 1), and provide quantitative estimates of tissue-specific RAL penetration relative to HIV persistence (via VRC01 and F-AraG, Aim 2). This mentored award will support the training of Dr. Deitchman in HIV pharmacology methods, and HIV viral and immune measures while informing dosing approaches for these and similar curative agents - methods that will serve as a model for PET-based evaluation of HIV therapeutics in future curative trials.