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HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System

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Abstract

Antiretroviral therapy (ART) has transformed HIV into a chronic condition, lengthening and improving the lives of individuals living with this virus. Despite successful suppression of HIV replication, people living with HIV (PLWH) are susceptible to a growing number of comorbidities, including neuroHIV that results from infection of the central nervous system (CNS). Alterations in the dopaminergic system have long been associated with HIV infection of the CNS. Studies indicate that changes in dopamine concentrations not only alter neurotransmission, but also significantly impact the function of immune cells, contributing to neuroinflammation and neuronal dysfunction. Monocytes/macrophages, which are a major target for HIV in the CNS, are responsive to dopamine. Therefore, defining more precisely the mechanisms by which dopamine acts on these cells, and the changes in cellular function elicited by this neurotransmitter are necessary to develop therapeutic strategies to treat neuroHIV. This is especially important for vulnerable populations of PLWH with chemically altered dopamine concentrations, such as individuals with substance use disorder (SUD), or aging individuals using dopamine-altering medications. The specific neuropathologic and neurocognitive consequences of increased CNS dopamine remain unclear. This is due to the complex nature of HIV neuropathogenesis, and logistical and technical challenges that contribute to inconsistencies among cohort studies, animal models and in vitro studies, as well as lack of demographic data and access to human CNS samples and cells. This review summarizes current understanding of the impact of dopamine on HIV neuropathogenesis, and proposes new experimental approaches to examine the role of dopamine in CNS HIV infection.

HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System. Both substance abuse disorders and the use of dopaminergic medications for age-related diseases are associated with changes in CNS dopamine concentrations and dopaminergic neurotransmission. These changes can lead to aberrant immune function, particularly in myeloid cells, which contributes to the neuroinflammation, neuropathology and dysfunctional neurotransmission observed in dopamine-rich regions in HIV+ individuals. These changes, which are seen despite the use antiretroviral therapy (ART), in turn lead to further dysregulation of the dopamine system. Thus, in individuals with elevated dopamine, the bi-directional interaction between aberrant dopaminergic neurotransmission and HIV infection creates a feedback loop contributing to HIV associated neurocognitive dysfunction and neuroHIV. However, the distinct contributions and interactions made by HIV infection, inflammatory mediators, ART, drugs of abuse, and age-related therapeutics are poorly understood. Defining more precisely the mechanisms by which these factors influence the development of neurological disease is critical to addressing the continued presence of neuroHIV in vulnerable populations, such as HIV-infected older adults or drug abusers. Due to the complexity of this system, understanding these effects will require a combination of novel experimental modalities in the context of ART. These will include more rigorous epidemiological studies, relevant animal models, and in vitro cellular and molecular mechanistic analysis.

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Abbreviations

ART:

antiretroviral therapy

BBB:

blood brain barrier

CNS:

0central nervous system

CSF:

cerebrospinal fluid

PLWH:

people living with HIV

SUD:

substance use disorder

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Acknowledgements

We greatly appreciate the thoughtful discussions of the ideas presented in this manuscript with all members of the Berman and Gaskill laboratories. This work was supported by grants from the National Institutes of Drug Abuse, DA039005 (PJG), DA049227 (PJG), DA041931 (JWB and TMC), DA044584 (JWB), DA048609 (JWB) and the National Institutes of Mental Health MH112391 (JWB and TMC) and T32MH079785 (Khalili), supporting EAN.

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  1. Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA

    E. A. Nickoloff-Bybel & P. J. Gaskill

  2. Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    T. M. Calderon & J. W. Berman

  3. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    J. W. Berman

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  1. E. A. Nickoloff-Bybel
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  2. T. M. Calderon
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  3. P. J. Gaskill
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  4. J. W. Berman
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All authors were involved in the conception, design, and drafting of the manuscript as well as the interpretation of relevant literature. All authors participated in editing the manuscript for important intellectual content, and all authors approved the final version to be submitted. All authors agree to be accountable for all aspects of the work to ensure that questions related to the accuracy or integrity of any part of the work are appropriately examined and resolved and declare to have confidence in the integrity of the contributions of their co-authors.

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Nickoloff-Bybel, E.A., Calderon, T.M., Gaskill, P.J. et al. HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System. J Neuroimmune Pharmacol 15, 729–742 (2020). https://doi.org/10.1007/s11481-020-09927-6

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