Imaging microglia in virally-suppressed HIV

About This Grant

PROJECT SUMMARY In spite of the benefits of antiretroviral therapy, the burden of central nervous system complications remains high among virally-suppressed people with human immunodeficiency virus (VS+PWH). Study of cognitive impairment across cohorts of VS+PWH often reveals subsets of VS+PWH with relatively marked, low performance in executive function (EF) that is now referred to as cognitive control (CC). This project aims to study regional proliferation of microglia, and the relationship to EF/CC in VS+PWH. Our focus on positron emission tomography (PET) imaging of microglia stems from our previous efforts. Our group validated use of [11C]DPA-713 (DPA) PET to localize a microglial marker of brain injury and repair, the translocator protein 18 kDa (TSPO) in human health and VS+PWH. Among 23 VS+PWH, high TSPO in prefrontal cortex or frontal cortex associated with low performance across select cognitive domains of memory, motor function, and EF/CC. Our subsequent study of VS+PWH (n=25) focused on the relationship between TSPO and EF/CC. Using DPA PET and a priori-defined regions relevant to EF/CC function, higher levels of TSPO in EF/CC regions were found in VS+PWH compared to HIV-CON. Higher TSPO in each EF/CC region showed association with higher self-reported burden of cognitive problems. Further, higher TSPO in the two EF/CC regions that subserve the EF/CC subdomain of response inhibition (lateral PFC, inferior parietal lobe) associated with lower performance in EF/CC response inhibition. Since TSPO is not microglia-specific in its expression, [11C]CPPC (CPPC) was developed to image the colony stimulating factor 1 receptor (CSF1R), which is chiefly expressed by microglia and myeloid cells. Using pilot design, CPPC brain PET demonstrated a trend of higher CSF1R in 16 VS+PWH relative to 15 HIV- uninfected controls (HIV-CON) including in EF/CC regions of PFC and parietal cortex. In VS+PWH, higher CSF1R in each EF/CC region (PFC, parietal cortex) associated with poorer performance on the Stroop test of EF/CC response inhibition and higher CSF1R in parietal cortex associated with higher peripheral blood signature of myeloid cell activation and proliferation. Building on prior findings, we will use CPPC PET cross-sectionally in VS+PWH and HIV-CON to study further the CSF1R that marks microglial proliferation, as well as its regional relationship to EF/CC (self-report and performance metrics) or other immune markers in circulating blood. Our team at University of Texas Southwestern Medical Center is positioned well to use CPPC PET in an ethnically diverse population of VS+PWH and HIV-CON. The proposed approach (clinical, biofluid and imaging) will complement our prior body of work using TSPO PET in VS+PWH. Further, we use the NIMH Research Domain Criteria framework to study EF/CC in VS+PWH. These data will characterize further the cross-sectional relationship between microglial proliferation, EF/CC, and peripheral myeloid immune markers in VS+PWH – toward strategies for longitudinal tracking of the hypothesized, detrimental microglial contribution to EF/CC and deployment of immune modulating and/or EF/CC-targeted therapies to improve cognitive health in VS+PWH.