ABSTRACT Currently, the lack of adequate animal models to replicate the events of HIV-1 infection in humans presents a critical barrier to study HIV pathology of the central nervous system (CNS). Eradicating HIV-1 infection has become a priority. Contemporary, highly active antiretroviral therapy (ART) has significantly prolonged the lives of those infected, but it has not resolved the incidence of HIV-associated neurocognitive disorders (HAND). HIV persists in the human hemato-lymphoid compartments and in the central nervous system (CNS). Persistent HIV reservoirs both in the periphery and CNS result in chronic inflammation and end-organ diseases. Clinical observations reveal that the virus is present in CNS-resident immune cells and in non-immune cells of the CNS, such as astrocytes. The CNS viral reservoir is life-long. Still, knowledge on the nature of persistent CNS viral reservoirs and their influence on neuroimmune homeostasis is limited because of deficiencies in existing small animal models. We aim to establish a new TRIPLE humanized mouse model reconstituted with autologous human blood/ hematolymphoid system, microglia, and astrocytes to study the interaction of peripheral HIV- infection and immune activation with human brain glial cells in developing CNS immune and neuronal dysfunction. Mice that possess both peripheral blood/immune cells and human brain cells (HuBB-mice) are expected to provide a comprehensive model to study NeuroAIDS. The model is best suitable to study the research areas that fall within the scope of the current RFA. Using the new HuBB-mice, we aim to study: 1). HIV glial reservoirs during suppressive ART and the dysregulation of neuroimmune homeostasis using single-cell transcriptomic analysis, and 2). the altered neuronal integrity and function as a consequence of dysregulated neuroimmune homeostasis. Animals treated with ART suppress peripheral viral replication in all tissues and cell types, including astrocytes and microglia, facilitating virologic, immunologic, and neuropathologic assessments. The proposed work is expected to lay the groundwork on the new HuBB-mice for future evaluations of multiple aspects of HAND pathology in the context of chronic infection/ immune activation, persistent HIV reservoirs in CNS, and neuroinflammation. The mouse model will be an important tool to develop therapeutics to alleviate HAND and for designing HIV eradication strategies from CNS reservoirs.

NARRATIVE People with HIV have a substantially elevated risk of developing cognitive impairment despite now having a life expectancy that approaches that of the general population. Persistent glial viral reservoirs and neuroinflammation are thought to be the factors contributing to HIV-associated neuronal impairments. A triple humanized mouse model reconstituted with human immune system, microglia and astrocytes will best recapitulate the dysfunction of neuro-immune homeostasis in relation to the persistent HIV reservoirs in central nervous system during suppressive antiretroviral therapy.