Development of novel In-vitro and In-vivo Models to support NeuroHIV Research

(Fast-Track and Direct to Phase 2 proposals will not be accepted) Number of anticipated awards: 1-3 Budget (total costs): Phase I: $300,000 for up to 1 year; Phase II: $2,000,000 for up to 2 years. Background Central Nervous System complications associated with HIV continues to persist in people with HIV (PWH) despite effective Page 128 Antiretroviral therapy (ART). Although excellent virologic control in the periphery and brain has been achieved, CNS disease (NeuroHIV) including neurologic, neurocognitive, and mental health problems are observed. Considerable gaps exist in our understanding of pathogenesis of CNS disease associated with HIV. Basic research in the NeuroHIV field has primarily focused on modeling neuronal damage in the context of active viral replication or the impact of HIV proteins such as Tat/gp120, with endpoints such as encephalitis and neuronal death. However, the CNS disease outcomes observed in the pre-ART era, such as atrophy and encephalitis, are not apparent in the current era. Other mechanisms, such as neuroimmune dysfunction, legacy effects of long-term ART medications and chronic inflammation, in the context of co-morbidities, may play a role in the observed HIVassociated CNS disease outcomes. Other potential unexplored mechanisms and pathways may drive the development of CNS disease, such as subtle neuro-metabolic changes, alterations in neuronal circuitry, or altered signal transmission. There is a need for novel model systems that will help better understand the Immune-Central Nervous System (CNS) interactions in the context of HIV.