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Exosomes and HIV Neuropathogenesis

NAMHC Concept Clearance

Presenter

Dianne Rausch, Ph.D.
Director, Division of AIDS Research

Goal

The goal of this initiative is to stimulate further research on the central role of exosomes in HIV-associated neurocognitive disorders (HAND). Specifically, this initiative encourages studies addressing the contribution of exosomes in modulating chronic inflammation in HAND, in addition to studies exploring the potential use of exosomes in the delivery of central nervous system (CNS)-targeted therapeutics.

Rationale

Despite excellent virologic control achieved by the widespread use of potent anti-retrovirals, HAND remains prevalent. Chronic low level inflammation likely plays a key role in this continued prevalence. Notably, there are considerable gaps in our understanding of the pathophysiologic mechanisms driving HAND in well-treated individuals. For example, there is great need to improve our understanding of the communication pathways between cells that contribute to the pathogenesis of HAND. In particular, it is important to understand the pathways between macrophages, astrocytes, and neuronal cells with regard to inflammatory mediators and regulators of gene expression, such as miRNAs, that lead to HAND. Defining these pathways is critical to understanding the mechanisms of HIV neuropathogenesis in the current treatment era.

Exosomes are cell-derived vesicles that are present in all biological fluids (e.g., blood, urine, cell culture medium). Exosomes can be released both in vivo and in vitro from a variety of cells including neuronal cells, microglia, astrocytes, and immune cells such as monocytes and lymphocytes. Exosomes contain the molecular constituents of their cells of origin, including proteins, RNA, and signaling complexes.

Importantly, exosomes have emerged as major conduit for cell-cell communication, and have been shown to play a role in other neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS). Specifically, exosomes are involved in the progression of neurodegenerative pathologies associated with misfolded proteins as potential carriers in pathological processes. For example, in Parkinson’s disease, exosomes play a key role in spreading the aggregated products of alpha-synuclein from neuron to neuron (resulting in cell death), and in propagating the inflammatory response from cell to cell. In ALS, astrocyte-derived exosomes efficiently transfer mutant superoxide dismutase to spinal neurons, inducing selective motor neuron death. These studies suggest that the neurodegenerative processes associated with HIV infection of the CNS, such as those in HAND, may also be modulated by exosomes.

The purpose of this initiative is to accomplish the following goals:

  • Assess the mechanisms of exosome release from CNS-derived cells in the setting of HIV infection (in vitro and in vivo).
  • Define exosomal cargo (e.g., inflammatory mediators, viral and host proteins, nucleic acids) derived from HIV-infected cells, and determine their potential impact on neuronal apoptosis.
  • Study gene regulation in CNS cells following exposure to exosomes released from HIV-infected cells.
  • Evaluate the potential role of exosomes as biomarkers for HAND progression and response to therapy.
  • Determine the utility of exosomes as delivery vehicles for CNS-targeted therapeutics.

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