Neutral sphingomyelinase 2 inhibition attenuates extracellular vesicle release and improves neurobehavioral deficits in murine HIV

Zhu, Xiaolei; Hollinger, Kristen R.; Huang, Yiyao; Borjabad, Alejandra; Kim, Boe-Hyun; Arab, Tanina; Thomas, Ajit G.; Moniruzzaman, Mohammed; Lovell, Lyndah; Turchinovich, Andrey; Witwer, Kenneth W.; Volsky, David J.; Haughey, Norman J.; Slusher, Barbara S.

doi:10.1016/j.nbd.2022.105734

Cited by 14 publications

(7 citation statements)

References 109 publications

(138 reference statements)

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“…The virus brain burdens were not stably altered in this study despite continuing insulin therapy and NCI improvement 10 suggesting that that some interventions can mitigate NCI without reducing brain HIV burdens. NCI reversal was also observed after treatment of EcoHIV-infected mice with the glutaminase antagonist JHU083 13 , potentially through restoration of physiological glutamate levels in the brain 12 , or a novel neutral sphingomyelinase inhibitor PDDC, the latter possibly through normalization of elevated ceramide and extracellular vesicles production found in EcoHIV infected mice and PLWH 64 . The NCI in the latter study was measured for the first time by the extent of psychiatric-like deficits 64 , adding to the range of neurocognitive deficits in EcoHIV infected mice resembling these seen in PLWH 36 .…”

Section: Discussionmentioning

confidence: 90%

“…NCI reversal was also observed after treatment of EcoHIV-infected mice with the glutaminase antagonist JHU083 13 , potentially through restoration of physiological glutamate levels in the brain 12 , or a novel neutral sphingomyelinase inhibitor PDDC, the latter possibly through normalization of elevated ceramide and extracellular vesicles production found in EcoHIV infected mice and PLWH 64 . The NCI in the latter study was measured for the first time by the extent of psychiatric-like deficits 64 , adding to the range of neurocognitive deficits in EcoHIV infected mice resembling these seen in PLWH 36 . Overall, these studies indicate that addressing dysregulated neurobiological functions in the brain at several levels can ameliorate HIV behavioral defects without eliminating brain HIV, suggesting the possibility of a functional cure of NCI.…”

Section: Discussionmentioning

confidence: 90%

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CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice

Kim

Hadas

Kelschenbach

et al. 2023

Sci Rep

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HIV enters the brain within days of infection causing neurocognitive impairment (NCI) in up to half of infected people despite suppressive antiretroviral therapy. The virus is believed to enter the brain in infected monocytes through chemotaxis to the major monocyte chemokine, CCL2, but the roles of CCL2 in established NCI are not fully defined. We addressed this question during infection of conventional and CCL2 knockout mice with EcoHIV in which NCI can be verified in behavioral tests. EcoHIV enters mouse brain within 5 days of infection, but NCI develops gradually with established cognitive disease starting 25 days after infection. CCL2 knockout mice infected by intraperitoneal injection of virus failed to develop brain infection and NCI. However, when EcoHIV was directly injected into the brain, CCL2 knockout mice developed NCI. Knockout of CCL2 or its principal receptor, CCR2, slightly reduced macrophage infection in culture. Treatment of mice prior to and during EcoHIV infection with the CCL2 transcriptional inhibitor, bindarit, prevented brain infection and NCI and reduced macrophage infection. In contrast, bindarit treatment of mice 4 weeks after infection affected neither brain virus burden nor NCI. Based on these findings we propose that HIV enters the brain mainly through infected monocytes but that resident brain cells are sufficient to maintain NCI. These findings suggest that NCI therapy must act within the brain.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 90%

CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice

Kim

Hadas

Kelschenbach

et al. 2023

Sci Rep

Self Cite

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“…and polyinosinicpolycytidylic acid (poly I:C) (12, 14-17). All of these target important processes in the development of HIV-NCI including brain glucose metabolism (13), brain glutamate metabolism (17), or brain exosome production (79). However, to our knowledge, buprenorphine is the first therapy that targets the migration of inflammatory monocytes into the CNS, a key process required for the establishment and maintenance of HIV-NCI.…”

Section: Discussionmentioning

confidence: 99%

Buprenorphine reverses neurocognitive impairment in EcoHIV infected mice: A potential therapy for HIV-NCI

Murphy

Kelschenbach

et al. 2022

Front. Immunol.

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Thirty-eight million people worldwide are living with HIV, PWH, a major public health problem. Antiretroviral therapy (ART) revolutionized HIV treatment and significantly increased the lifespan of PWH. However, approximately 15-50% of PWH develop HIV associated neurocognitive disorders (HIV-NCI), a spectrum of cognitive deficits, that negatively impact quality of life. Many PWH also have opioid use disorder (OUD), and studies in animal models of HIV infection as well as in PWH suggest that OUD can contribute to HIV-NCI. The synthetic opioid agonist, buprenorphine, treats OUD but its effects on HIV-NCI are unclear. We reported that human mature inflammatory monocytes express the opioid receptors MOR and KOR, and that buprenorphine reduces important steps in monocyte transmigration. Monocytes also serve as HIV reservoirs despite effective ART, enter the brain, and contribute to HIV brain disease. Using EcoHIV infected mice, an established model of HIV infection and HIV-NCI, we previously showed that pretreatment of mice prior to EcoHIV infection reduces mouse monocyte entry into the brain and prevents NCI. Here we show that buprenorphine treatment of EcoHIV infected mice with already established chronic NCI completely reverses the disease. Disease reversal was associated with a significant reduction in brain inflammatory monocytes and reversal of dendritic injury in the cortex and hippocampus. These results suggest that HIV-NCI persistence may require a continuing influx of inflammatory monocytes into the brain. Thus, we recommend buprenorphine as a potential therapy for mitigation of HIV brain disease in PWH with or without OUD.

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“…184 Further inhibition of sphingomyelinase 2 reduced both the depressive symptoms and the levels of the above-mentioned miRNAs, suggesting an indirect link between the two. 185 Though a direct correlation is yet to be established, it is clear that EVs can also be used to monitor depressive phenotypes in HIV patients.…”

Section: Neuropsychiatric Disorders 331 Depressionmentioning

confidence: 99%

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications

Onkar,

Khan,

Goenka

et al. 2024

ACS Appl. Mater. Interfaces

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Information exchange is essential for the brain, where it communicates the physiological and pathological signals to the periphery and vice versa. Extracellular vesicles (EVs) are a heterogeneous group of membrane-bound cellular informants actively transferring informative calls to and from the brain via lipids, proteins, and nucleic acid cargos. In recent years, EVs have also been widely used to understand brain function, given their "cell-like" properties. On the one hand, the presence of neuron and astrocyte-derived EVs in biological fluids have been exploited as biomarkers to understand the mechanisms and progression of multiple neurological disorders; on the other, EVs have been used in designing targeted therapies due to their potential to cross the blood-brain-barrier (BBB). Despite the expanding literature on EVs in the context of central nervous system (CNS) physiology and related disorders, a comprehensive compilation of the existing knowledge still needs to be made available. In the current review, we provide a detailed insight into the multifaceted role of brain-derived extracellular vesicles (BDEVs) in the intricate regulation of brain physiology. Our focus extends to the significance of these EVs in a spectrum of disorders, including brain tumors, neurodegenerative conditions, neuropsychiatric diseases, autoimmune disorders, and others. Throughout the review, parallels are drawn for using EVs as biomarkers for various disorders, evaluating their utility in early detection and monitoring. Additionally, we discuss the promising prospects of utilizing EVs in targeted therapy while acknowledging the existing limitations and challenges associated with their applications in clinical scenarios. A foundational comprehension of the current state-of-the-art in EV research is essential for informing the design of future studies.

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Neutral sphingomyelinase 2 inhibition attenuates extracellular vesicle release and improves neurobehavioral deficits in murine HIV

Cited by 14 publications

References 109 publications

CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice

CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice

Buprenorphine reverses neurocognitive impairment in EcoHIV infected mice: A potential therapy for HIV-NCI

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications

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