Astrocyte-derived exosomes contribute to HIV neuropathogenesis.

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Abstract HIV infection has become a chronic disease, with the improved quality of life of people with HIV (PWH) thanks to the efficacy of antiretroviral therapy. Due to chronic inflammation, viral entry into the central nervous system, disruption of brain homeostasis and aging, 50% of PWH are at risk of developing HIV-associated cognitive impairment (HIV-CI). Astrocytes regulate and maintain neuronal activity and brain homeostasis, and thus become reactive in response to inflammation. Although productive infection of astrocytes with HIV is still a matter of debate, it has been demonstrated that these cells can be infected with HIV, shed virus to the periphery, and may be important HIV reservoirs. We have found that exosomes from astrocytes are present and significantly higher in plasma of PWH, and are significantly associated with greater reactive oxygen species (ROS) levels in those with cognitive impairment. This finding confirms communication between the brain and the periphery in NeuroHIV driven by astrocytes. In addition, we have detected the insulin receptor in plasma exosomes from PWH, significantly higher in cognitive impaired patients and positively correlating with exosomal HIV Tat protein and exosomal ROS levels. Therefore, astrocytes not only play a role in HIV infection by the establishment of viral reservoirs and communication with the periphery in PWH, but may also be regulating glucose, insulin signaling, and metabolic processes in the brain of PWH. We hypothesize that upon HIV infection, astrocytes become proinflammatory, altering their insulin signaling in the CNS, and contributing to the development of HIV-CI. In the process, astrocytes release exosomes to the plasma that may contain signatures, such as insulin receptor (among others), which would lead us to uncover astrocyte-specific insulin- related mechanisms occurring in PWH using ART. We propose, 1. Characterize the cargo of astrocyte-derived exosomes from the plasma and CSF of PWH and their association to HIV-associated cognitive impairment (HIV-CI). 2. Determine and compare the phenotype of astrocytes exposed to cell-free HIV, plasma and CSF from PWH in vitro. 3. Explore the effect of the astrocyte-derived exosomes on neuronal function. We will explore astrocyte phenotype and differentially activated pathways in response to plasma and CSF from PWH using ART with emphasis on insulin signaling and astrocyte-derived exosomes.