Abstract Approximately half of the roughly 40 million people with HIV (PHIV) worldwide develop HIV associated neurocognitive disorders (HAND), regardless of whether they receive combined antiretroviral therapy (cART). Mild forms of HAND, which are most common in PHIV on cART, ultimately progress to dementia. Treatment strategies to eradicate HIV are ongoing, but in reality the brain will remain an HIV reservoir for the foreseeable future. Therefore, developing adjunctive treatments for HAND is important while simultaneously advancing eradication strategies. Another important point is targeting treatments to mild forms of HAND [prior to dementia], when treatment is more likely to stabilize or reverse HAND. To best accomplish this, an animal model must be used that is practical, displays cognitive deficits and pathology consistent with mild HAND in humans, and preferably employs replicating HIV so that long-term effects of treatments and eradication strategies can be optimally investigated. However, currently there is no model that incorporates all of these important features. Recently it has been shown that humanized (BLT) mouse models of HIV infection exhibit trafficking of human cells to mouse brain, including T cells and mononuclear phagocytes (MP), which are the cell types infected by HIV. HIV-infected human MP and T cells have been demonstrated in BLT brains, HIV DNA and RNA can be quantitated in brain, and there is a mouse MP reaction similar that seen in humans with mild HAND. Importantly the BLT model exhibits long lived brain infection, which enables testing of novel treatments in sufficient numbers of animals to determine statistically significant, prolonged effects and tolerability in BLT mice that can also be simultaneously treated with cART. However, BLT mice have not been shown to have cognitive deficits or neuronal abnormalities, which are hallmarks of HAND. The proposed studies will test BLT mice for cognitive deficits using techniques that are established in our current short term SCID mouse HAND model. Essential pathological parameters to be monitored will be brain HIV load, mouse and human brain MP inflammatory activity, and neuronal dendritic integrity in important regions such as frontal cortex, hippocampus and the basal ganglia. These are also established techniques in our current short-term HAND model. Therefore, the first aim is to validate the BLT model according to important features of HAND including cognitive deficits and associated neuronal pathology. The second major aim of the proposal is to validate novel treatments previously shown to be effective in the short-term HAND model with long-term testing for efficacy in HAND, safety and potentially brain HIV eradication. It is predicted that this model will be validated along with novel treatments as detailed in the proposal, providing a direct conduit to human clinical trials.