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Deciphering Neuroimmune Dysfunction in HIV Utilizing Human Cell Derived in vitro and in vivo Systems

NAMHC Concept Clearance

Presenter:

Vasudev Rao, M.B.B.S, M.S. and Dianne Rausch, Ph.D.
Division of AIDS Research

Goal:

This concept aims to support studies to better comprehend HIV associated central nervous system (CNS) dysfunction in people living with HIV (PLHIV) on antiretroviral therapy (ART) utilizing human cell-derived in vitro and in vivo model systems.

Rationale:

In the United States and globally, CNS comorbidities associated with HIV, including neurologic, neurocognitive, and mental health problems, continue to persist in PLHIV despite effective ART. Considerable gaps exist in the understanding of CNS comorbidities associated with HIV in the context of ART as the majority of basic research in the NeuroHIV field has focused on studying outcomes that were important in the context of active viral replication. Immune dysfunction and chronic immune activation associated with HIV in PLHIV on ART have been hypothesized to be the primary drivers of CNS comorbidities. There is a need to comprehend the pathophysiology of HIV associated CNS comorbidities by causally linking HIV associated immune dysfunction and chronic immune activation with cellular, synaptic, and circuit-related neuronal processes using a convergent neuroscience approach.

Over the past decade, scientists have developed several human-cell-derived in vitro and in vivo models to better understand HIV reservoirs and cures. Also, the neuroscience field has seen development of novel in vivo models that incorporate human immune and neuronal cells such as brain organoids. Such novel brain organoids and humanized animal models can facilitate mechanistic studies of immune-CNS interactions incorporating factors such as chronicity of viral infection, viral suppression, legacy effects, impact of ART and other conditions that are observed in people living with HIV. Studies developed using such human immune cell derived systems have the potential to significantly enhance our understanding of the causal linkages of immune-related CNS outcomes not only among PLHIV but also in the general population.

Examples of work supported (Including but not limited to)

  • Studies to determine the modulatory effects of immune dysfunction and chronic inflammatory changes caused by HIV in the context of ART on neuronal circuits, neurotransmitters, and their connections with other systems, such as the hypothalamic-pituitary-adrenal axis and the neuroendocrine system
  • Studies that model the impact of chronic immune activation and immune dysfunction in the periphery caused by HIV and ART on the blood-brain barrier and its impact on neuronal function
  • Studies to identify pre-clinical drug targets that can alter the neurobehavioral consequences of immune dysfunction and chronic inflammation in the periphery and CNS caused by HIV and ART
  • Studies to identify the impact of persistent viral reservoirs in the CNS on neurotransmitters, neuronal function, and neuronal plasticity