Abstract This competitive renewal for 5 R01 NS034239 now in its 27th year provides a research plan reflecting the National Institutes of Health strategic plan for HIV and HIV-related research. The plan lists neurologic complications as a primary study need. The current study seeks to investigate the interplay between aging, HIV-1 infection, and neurodegenerative diseases. The preliminary data now offered targets a significant need in biomedical research for neuroHIV. That need is the discovery and characterization of a viable animal models that would mimic the neuropathobiology of HIV-1 infection in the setting of Alzheimer’s disease (AD). It was previously not possible to study a dynamic interplay between viral infection of CD4+ T cell subsets, immunity, antiretroviral therapy (ART), and AD. We solved that problem as during the last grant cycle we created the needed model. Herein, we provide extensive data of its utility, have outlined viable experimental approaches, and affirm its significance to provide significant new insights into better understanding disease mechanisms and potential therapeutics that can be realized during the 28th to the 33rd year of the project. The proposed work rests on a sound research foundation by building on fundamental research findings made during the prior granting cycle. During that time we showed that amyloid β (Aβ)-specific helper T cell type-1 (Th1) and -17 (Th17) effector T cell (Teff) clones propel neurotoxic innate neuroinflammatory responses, proteinopathy, and neuronal dysfunction that were associated with cognitive impairment in amyloid precursor protein transgenic mice. Moreover, through parallel studies, we demonstrated that regulatory T cells (Treg) attenuate neuroinflammation and AD neuropathology, then restore cognitive function. With our novel AD humanized mice in hand, we now show that during HIV-1 infection we not simply see increases in neuroinflammation but that viral immune response can facilitates proteinopathy. We are now able to conduct studies of HIV-1 compartmentalization, virus-amyloid adaptive and innate immunity alterations, and consequences of immune-pathogenic and regulatory events. These can serve both to accelerate or ameliorate AD processes. The aims of the proposal will be to fully characterize the model at the cell, immune, tissue, and disease level by studies of innate macrophage-microglia and adaptive CD4+ Teffs pro-inflammatory factors known to affect the brain’s microenvironment. The second component will assess immune transformation by a spectrum of therapeutic agents that include antiretroviral therapy. We will now directly interrogate how T cell immunity drives the tempo of both HIV/AIDS in the setting of neurodegenerative disease. Finally, Tregs that are engineered to recognize Aβ by a transgenic T cell receptor (TCR) or a chimeric antigen receptor (CAR), will be employed as “future” therapeutic strategies to restore brain homeostasis, reduce plaque burden, and affect n...