[F31] HIV-induced trained immunity in microglia and its contribution to HAND pathogenesis

Ente: National Institute of Mental Health

Scadenza: 2028-06-18

Importo max: 50.114 EUR

Paese: US

Descrizione

Despite the widespread use of antiretroviral therapy (ART), it is estimated that up to 50% of people living with HIV (PLWH) experience HIV-associated neurocognitive disorders (HAND). HAND decreases quality of life but critically, progression to more severe forms like HIV-associated dementia (HAD) often occurs, especially with increasing age. Associations between neuroinflammation and HAND are known to exist, but the molecular mechanisms driving this are poorly understood. Recently, it has been established that previous inflammatory insults can alter the response of innate immune cells to subsequent inflammatory stimuli, a concept termed innate immune memory (IIM). Trained immunity (TI) is an IIM phenotype classified by hyperresponsiveness to secondary stimulation and is established through epigenetic and metabolic reprogramming. TI is protective in the context of repeated acute insults, but maladaptive in chronic disease. Multiple published studies have suggested that TI occurs in peripheral myeloid cells of PLWH, but whether this occurs in microglia remains unexplored. Preliminary data in the C20 microglial cell line has suggested exposure to HIV-1 induces TI. In addition, multiple reported microglia gene expression signatures in the context of HIV-1 align with trained microglia signatures in other contexts. If TI is established in microglia of PLWH, the characteristic hyperresponsiveness to inflammatory insult could exacerbate neuroinflammation, driving establishment or progression of HAND. Further, TI-like epigenetic reprogramming is known to persist despite cure from other diseases of viral etiology such as hepatitis C virus (HCV), where “epigenetic scarring” drives persistent chronic inflammation and increased liver cancer risk despite virus eradication. Similarly, chronic neuroinflammation and HAND could persist despite HIV cure due to long-lived microglia remaining in the trained state. This possibility, along with the implications of TI in HAND pathogenesis, warrants scientific inquiry into the mechanisms and functional outcomes of HIV-1-induced TI in microglia. In Aim 1, a novel in vitro TI model will be established in human monocyte-derived microglia (MDMi), solving the long- standing issue of lacking physiologically relevant models in the broader microglia TI field. Using this model, HIV- derived molecular inducers of TI will be identified, and epigenetic and metabolic mechanisms of HIV-induced TI will be elucidated utilizing chromatin immunoprecipitation (ChIP) and Seahorse metabolic assays. In Aim 2, the functional outcomes of HIV-1 induced TI will be explored through investigation of perturbations in phagocytic capacity, ROS production, iNOS activity, and microglia morphology. Further, RNA-sequencing will generate transcriptomic signatures of HIV-trained microglia, aiding in elucidation of therapeutic targets and identification of biomarkers for HIV-trained microglia. The proposed fellowship training plan integrates advanced technic Istituzione: DREXEL UNIVERSITY PI: Zachary Capriotti Progetto: 1F31MH144977-01

Settori: National Institute of Mental Health

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