In Vivo Imaging and Post-Mortem Study of Methamphetamine Use on Immune Dysfunction and HIV Reservoir Transcription among People with HIV on ART - SUMMARY/ABSTRACT Despite higher burden of methamphetamine (MA) use in people with HIV (PWH), very little is known about the impact of MA on HIV persistence, viral-host responses, immune cell activation, and end-organ damage, particularly in the central nervous system (CNS) and cardiovascular system (CVS). MA use has primarily been studied in the setting of untreated HIV, and no study to date has linked MA use directly with increased HIV transcription, tissue inflammation, immune dysregulation, and clinical outcomes during adequate ART suppression. An increasing body of literature suggests that eradication of residual virus may be necessary to improve clinical outcomes, and the impact of MA use in treated HIV on host tissue responses across the whole body that lead to tissue inflammation and damage is unknown. Our proposed RM1 will test the central hypothesis that MA induces HIV-1 transcription, even during suppressive ART, which then serves to trigger abnormal host immune activation, inflammation, and increased morbidity from the additive effects of both virus and drug use. The combined negative impact of MA and HIV-1 on the CNS and CVS, as these are areas of major clinical concern among people who use MA, and tissue damage may persist even after cessation of active drug use. An in-depth understanding of the longitudinal pathophysiology and host responses to MA use is a critical unmet need that will inform the discovery of novel therapeutic targets to reduce immune dysfunction, HIV-1 persistence and inflammation, and improve clinical outcomes and chances of HIV cure in this population. We have assembled a highly collaborative team to apply innovative, multidisciplinary tools to address the fundamental gaps in the understanding of the pathophysiological underpinnings of HIV persistence and organ damage in the setting of MA use. This unified and highly synergistic approach leverages three unique cohorts that we have developed over the past decade to test our overall hypothesis, performing the first-in-human studies directly quantifying MA concentrations in blood, CSF, and tissues of PWH on ART in relation to HIV persistence and host inflammation in the CNS and CVS: (1) a longitudinal observational tissue, blood and cerebral spinal fluid (CSF) sampling study of PWH on ART with chronic MA use; (2) an interventional study administering short-term oral MA to PWH on ART without a history of MA use disorder; and (3) the world’s first POST SCD study of autopsy specimens across the whole body from PWH on ART and toxicologically proven MA use. We will employ innovative methods, including performing whole-body PET imaging of the HIV-1 reservoir and myeloid/microglial activation, multi-omic assays to characterize the host immune response, pharmacodynamic analyses of MA, and high-resolution measures of the HIV reservoir from longitudinal blood, cerebral spinal fluid, gut and lymphoid samples. A pathophysiological understanding of these processes is essential for the discovery and targeting of novel pathways to reduce clinical morbidity and will pave the way for targeted clinical interventions or screening in PWH with MA use.
