HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System

Nickoloff-Bybel, Emily A; Calderon, Tina M.; Gaskill, Peter J.; Berman, Joan W.

doi:10.1007/s11481-020-09927-6

Cited by 30 publications

(22 citation statements)

References 216 publications

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“…HIV-1 has been shown to exert damage to dopaminergic cells and cause synaptic connectivity loss in dopaminergic projection pathways (91), presenting frequently in infected individuals as apathy and motivation dysregulation (92,93). These behavioral sequelae of HAND are accompanied by increased markers of inflammation in the striatum (94).…”

Section: Discussionmentioning

confidence: 99%

Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat

et al. 2021

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While current therapeutic strategies for people living with human immunodeficiency virus type 1 (HIV-1) suppress virus replication peripherally, viral proteins such as transactivator of transcription (Tat) enter the central nervous system early upon infection and contribute to chronic inflammatory conditions even alongside antiretroviral treatment. As demand grows for supplemental strategies to combat virus-associated pathology presenting frequently as HIV-associated neurocognitive disorders (HAND), the present study aimed to characterize the potential utility of inhibiting monoacylglycerol lipase (MAGL) activity to increase inhibitory activity at cannabinoid receptor-type 1 receptors through upregulation of 2-arachidonoylglycerol (2-AG) and downregulation of its degradation into proinflammatory metabolite arachidonic acid (AA). The MAGL inhibitor MJN110 significantly reduced intracellular calcium and increased dendritic branching complexity in Tat-treated primary frontal cortex neuron cultures. Chronic MJN110 administration in vivo increased 2-AG levels in the prefrontal cortex (PFC) and striatum across Tat(+) and Tat(–) groups and restored PFC N-arachidonoylethanolamine (AEA) levels in Tat(+) subjects. While Tat expression significantly increased rate of reward-related behavioral task acquisition in a novel discriminative stimulus learning and cognitive flexibility assay, MJN110 altered reversal acquisition specifically in Tat(+) mice to rates indistinguishable from Tat(–) controls. Collectively, our results suggest a neuroprotective role of MAGL inhibition in reducing neuronal hyperexcitability, restoring dendritic arborization complexity, and mitigating neurocognitive alterations driven by viral proteins associated with latent HIV-1 infection.

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Section: Discussionmentioning

confidence: 99%

Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat

et al. 2021

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“…Although some evidence suggests that HIV neurotoxins may directly modulate the dopamine transporter and damage brain areas with high dopamine expression [ 68 ], drug abuse is another common comorbidity that can transiently elevate dopamine levels in HAND patients [ 69 ]. This can lead to several outcomes, including circuit adaptations and neuroinflammation in dopamine-rich regions [ 70 ], which may further contribute to synaptodendritic damage. Future studies that explore both excitatory and inhibitory systems in parallel as well as the status of other neuromodulators may help to provide a more integrated picture of neurotransmitter systems in the presence of HIV or other related factors.…”

Section: Neuroimaging and Neuropathological Studies In Hand Patientsmentioning

confidence: 99%

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

Irollo

Luchetta

et al. 2021

Cell. Mol. Life Sci.

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HIV-associated neurocognitive disorder (HAND) is characterized by cognitive and behavioral deficits in people living with HIV. HAND is still common in patients that take antiretroviral therapies, although they tend to present with less severe symptoms. The continued prevalence of HAND in treated patients is a major therapeutic challenge, as even minor cognitive impairment decreases patient’s quality of life. Therefore, modern HAND research aims to broaden our understanding of the mechanisms that drive cognitive impairment in people with HIV and identify promising molecular pathways and targets that could be exploited therapeutically. Recent studies suggest that HAND in treated patients is at least partially induced by subtle synaptodendritic damage and disruption of neuronal networks in brain areas that mediate learning, memory, and executive functions. Although the causes of subtle neuronal dysfunction are varied, reversing synaptodendritic damage in animal models restores cognitive function and thus highlights a promising therapeutic approach. In this review, we examine evidence of synaptodendritic damage and disrupted neuronal connectivity in HAND from clinical neuroimaging and neuropathology studies and discuss studies in HAND models that define structural and functional impairment of neurotransmission. Then, we report molecular pathways, mechanisms, and comorbidities involved in this neuronal dysfunction, discuss new approaches to reverse neuronal damage, and highlight current gaps in knowledge. Continued research on the manifestation and mechanisms of synaptic injury and network dysfunction in HAND patients and experimental models will be critical if we are to develop safe and effective therapies that reverse subtle neuropathology and cognitive impairment.

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“…Thus, cART is not a cure, although it does dramatically lengthen the quality and quantity of life for chronically HIV infected individuals [ 3 , 54 , 55 , 61 ]. Further, the use of cART has also created new health issues, as PLWH suffer from a variety of new comorbidities associated with chronic infection and long-term therapy [ 62 – 66 ].…”

Section: Hiv Pathogenesismentioning

confidence: 99%

“…Prior to cART, HIV-associated neuropathology was characterized by the formation of multinucleated giant cells, presence of microglial nodules, infiltration of lymphocytes, activated CNS macrophages, and neuronal loss [ 87 , 107 , 117 – 120 ]. These effects were particularly prominent in dopamine-rich brain regions, specifically in the substantia nigra, prefrontal cortex (PFC) and striatal substructures including the caudate nucleus, putamen, and nucleus accumbens [ 57 , 66 , 87 , 121 – 125 ]. Severe behavioral and cognitive symptoms were common [ 118 , 120 , 126 ], and some studies found HIV encephalitis (HIVE) in more than 50% of infected individuals [ 119 , 127 ].…”

Section: Hiv Pathogenesismentioning

confidence: 99%

Co-receptor signaling in the pathogenesis of neuroHIV

et al. 2021

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The HIV co-receptors, CCR5 and CXCR4, are necessary for HIV entry into target cells, interacting with the HIV envelope protein, gp120, to initiate several signaling cascades thought to be important to the entry process. Co-receptor signaling may also promote the development of neuroHIV by contributing to both persistent neuroinflammation and indirect neurotoxicity. But despite the critical importance of CXCR4 and CCR5 signaling to HIV pathogenesis, there is only one therapeutic (the CCR5 inhibitor Maraviroc) that targets these receptors. Moreover, our understanding of co-receptor signaling in the specific context of neuroHIV is relatively poor. Research into co-receptor signaling has largely stalled in the past decade, possibly owing to the complexity of the signaling cascades and functions mediated by these receptors. Examining the many signaling pathways triggered by co-receptor activation has been challenging due to the lack of specific molecular tools targeting many of the proteins involved in these pathways and the wide array of model systems used across these experiments. Studies examining the impact of co-receptor signaling on HIV neuropathogenesis often show activation of multiple overlapping pathways by similar stimuli, leading to contradictory data on the effects of co-receptor activation. To address this, we will broadly review HIV infection and neuropathogenesis, examine different co-receptor mediated signaling pathways and functions, then discuss the HIV mediated signaling and the differences between activation induced by HIV and cognate ligands. We will assess the specific effects of co-receptor activation on neuropathogenesis, focusing on neuroinflammation. We will also explore how the use of substances of abuse, which are highly prevalent in people living with HIV, can exacerbate the neuropathogenic effects of co-receptor signaling. Finally, we will discuss the current state of therapeutics targeting co-receptors, highlighting challenges the field has faced and areas in which research into co-receptor signaling would yield the most therapeutic benefit in the context of HIV infection. This discussion will provide a comprehensive overview of what is known and what remains to be explored in regard to co-receptor signaling and HIV infection, and will emphasize the potential value of HIV co-receptors as a target for future therapeutic development.

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HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System

Cited by 30 publications

References 216 publications

Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat

Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

Co-receptor signaling in the pathogenesis of neuroHIV

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