Estrogen regulation of age and PTSD-associated changes in macrophage-induced neuroinflammation during HIV infection.

30-50% of persons living with HIV still suffer from neurological co-morbidities, including HIV-associated Neurocognitive Disorders (HAND) and Post-traumatic stress disorder (PTSD), despite the success of combined Antiretroviral Therapy (cART). Persistent macrophage and microglia driven neuroinflammation is seen as a common underlying factor in HAND and PTSD disease progression. The long-term objective of this research is to understand the underling mechanisms that influence neuroinflammatory processes in neurological disorders to target more specific endogenous signaling mechanisms for development of novel therapeutic approaches. In this study we will explore estrogen signaling in macrophages and microglia as a possible therapeutic target. 17β- estradiol, the most active form of estrogen, is reduced in postmenopausal women. Studies have shown that 17β- estradiol is neuroprotective and its reduced expression may correlate with worse HIV and PTSD disease progression. However, how changes in estrogen concentrations and its receptors may modulate HIV-induced neurocognitive impairment in the post-menopausal women living with PTSD is unknown. Therefore, we hypothesize that macrophage and microglia induced neuroinflammation will be suppressed by estrogen, in an GPER dependent manner, in the aging female compared to males and pre-menopausal females living with Post-traumatic stress disorder and HIV. To address this hypothesis, we will utilize 2 in vitro HIV neuroinflammatory models: 1. A co-culture system composed of rat cortical neurons and human monocytes derived macrophages isolated from PTSD donors and 2. A co-culture system of iMicroglia and iNeurons derived from human pluripotent stem cells from healthy donors. iMicroglia and macrophages from pre and postmenopausal women and aged matched men will be pretreated with various concentrations of estrogen prior to HIVADA exposure to explore the following Specific Aims: 1) Evaluate estrogen’s ability to suppress HIV- induced neuroinflammation in PTSD-hMDM and Microglia. 2) Evaluate the role of estrogen receptors in HIV and PTSD-induced neuroinflammation. In this proposed award, we expect hMDMs from post-menopausal female PTSD donors and iMicroglia will have increased HIV-induced neuroinflammation, which can be suppressed by GPER activation. The PI has developed a strong training plan that will expand her expertise in the NeuroAIDS and PTSD field, increase her skillset in the generation of iPSC, flow cytometry, mass cytometry, biostatistical analysis and generate data for future R awards. This training will be guided by the strong mentoring committee of investigators from Spelman College and neighboring Research 1 institutions. With success of this project, we will elucidate the role of estrogen signaling as a potential endogenous targeted therapeutic avenue for persons living with HAND, PTSD and other neuroinflammatory disorders.