Anti-retroviral therapy (ART) for human immunodeficiency virus (HIV)-1 infection has prolonged and improved quality and longevity of life. Nonetheless, disease morbidities associated with HIV abound, including cognitive dysfunction (HIV associated dementia, HAD, and minor cognitive movement disorders, MCMD, among others) seen during the later stages of the disease. Thus, as infected people live well into their 60's and beyond they will more commonly face the ravages of neurodegenerative diseases. Currently, it is poorly understood how diseases such as Alzheimer's disease (AD) will be affected by chronic viral infection and how chronic viral infection will alter the tempo and progression of AD. We hypothesize that chronic neuroinflammation mediated by virus-infected mononuclear phagocytes (MP;perivascular macrophages and microglia) can accelerate the onset of AD. We propose developing animal models of beta-amyloidosis in HIV infected brains. We will specifically focus on the role of HIV-1 and neuroinflammation mediators, such as pro-inflammatory cytokines and chemokines, on Aj3 production from neurons and astrocytes, Aj3 degradation by microglia, and Aj3 oligomer formation and deposition in the brain. The study is significant. since we can evaluate the effect of HIV-1-infected microglia on AD pathogenesis. The animal models will be studied by multifaceted analysis to characterize the disease pathogenesis, including neuroinflammation, Aj3-related neuropathology, j3-amyloid precursor protein (APP) processing and aggregation, and Aj3 degrading enzyme cascade.
Two specific aims are proposed in this grant application. 1) To investigate the putative roles played by chronic HIV-1 infection on Aj3 synthesis and metabolism in human monocyte-derived macrophages (MDM);2) To characterize the role of persistent viral infection on beta-amyloidosis in severely compromised immunodeficiency mice expressing transgenic APP intracranially reconstituted with HIV-infected human MDM. We will specifically focus on the effect of viral proteins and pro-inflammatory cytokines, and intracellular signaling on regulation of Aj3 synthesis and clearance in two experimental paradigms. The study is significant in developing a preclinical model and elucidating the disease mechanism for early on set of AD in chronic AIDS patients, which will be useful for their prognosis, prevention, and therapy.
