Increases in CSF dopamine in HIV patients are due to the dopamine transporter 10/10-repeat allele which is more frequent in HIV-infected individuals

Horn, Anne; Scheller, Carsten; Plessis, Stéfan du; Arendt, Gabriele; Nolting, Thorsten; Joska, John A.; Sopper, Sieghart; Maschke, Matthias; Obermann, Mark; Husstedt, Ingo W.; Hain, Johannes; Maponga, Tongai; Riederer, Peter; Koutsilieri, Eleni

doi:10.1007/s00702-013-1086-x

Cited by 27 publications

(22 citation statements)

References 40 publications

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“…Some studies show dopamine and dopamine metabolites are reduced in postmortem brains from HIV infected individuals [153] – [155] and in the CSF of HIV+ individuals with late stage disease [156] – [159] . However, another study showed increased CNS dopamine in the CSF of therapy-naive, HIV-infected people in early stage disease [160] , [161] . Postmortem data from individuals with HIV encephalitis also suggested increased dopaminergic tone in the striatum [162] .…”

Section: Discussionmentioning

confidence: 99%

Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

et al. 2014

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Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers.

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Section: Discussionmentioning

confidence: 99%

Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

et al. 2014

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“…A strong correlation between a specific allele of the dopamine transporter (DAT), DAT 10/10, and HIV infection was found in German and African cohorts of HIV-positive and negative individuals. Individuals with the DAT10/10 allele, whether or not they were infected, showed higher baseline levels of CSF dopamine, suggesting that elevated dopamine is involved in HIV infection [134]. They also showed these changes in CSF dopamine and HIV infection were not correlated with genetic polymorphisms in catechol-O-methyltransferase (COMT, Val158Met), an enzyme involved in catecholamine metabolism, and dopamine receptors DRD2, DRD3, and DRD4 [135], although the specific DRD polymorphisms investigated were not the same as those mentioned above.…”

Section: Hiv Neuropathogenesis In the Cart Eramentioning

confidence: 99%

The role of catecholamines in HIV neuropathogenesis

Nolan

Gaskill

2019

Brain Research

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The success of anti-retroviral therapy has improved the quality of life and lifespan of HIV + individuals, transforming HIV infection into a chronic condition. These improvements have come with a cost, as chronic HIV infection and long-term therapy have resulted in the emergence of a number of new pathologies. This includes a variety of the neuropathological and neurocognitive effects collectively known as HIVassociated neurocognitive disorders (HAND) or NeuroHIV. These effects persist even in the absence of viral replication, suggesting that they are mediated the long-term changes in the CNS induced by HIV infection rather than by active replication. Among these effects are significant changes in catecholaminergic neurotransmission, especially in dopaminergic brain regions. In HIV-infected individuals not treated with ARV show prominent neuropathology is common in dopamine-rich brain regions and altered autonomic nervous system activity. Even infected individuals on therapy, there is significant dopaminergic neuropathology, and elevated stress and norepinephrine levels correlate with a decreased effectiveness of antiretroviral drugs. As catecholamines function as immunomodulatory factors, the resultant dysregulation of catecholaminergic tone could substantially alter the development of HIVassociated neuroinflammation and neuropathology. In this review, we discuss the role of catecholamines in the etiology of HIV neuropathogenesis. Providing a comprehensive examination of what is known about these molecules in the context of HIV-associated disease demonstrates the importance of further studies in this area, and may open the door to new therapeutic strategies that specifically ameliorate the effects of catecholaminergic dysregulation on NeuroHIV.

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“…Even in the era of cART, several studies have shown HIV infection alters dopamine concentrations and metabolism in the brain (Horn et al, 2013; Kumar et al, 2009; Kumar et al, 2011; Meulendyke et al, 2014; Scheller et al, 2010). Elevated dopamine has been shown to increase HIV infection of macrophages, the primary target for and source of HIV in the CNS (Gaskill et.…”

Section: Dopaminergic Neurotransmission Hiv Infection and Tatmentioning

confidence: 99%

HIV, Tat and dopamine transmission

Gaskill

Miller

Gamble-George

et al. 2017

Neurobiology of Disease

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Human Immunodeficiency Virus (HIV) is a progressive infection that targets the immune system, affecting more than 37 million people around the world. While combinatorial antiretroviral therapy (cART) has lowered mortality rates and improved quality of life in infected individuals, the prevalence of HIV associated neurocognitive disorders is increasing and HIV associated cognitive decline remains prevalent. Recent research has suggested that HIV accessory proteins may be involved in this decline, and several studies have indicated that the HIV protein transactivator of transcription (Tat) can disrupt normal neuronal and glial function. Specifically, data indicate that Tat may directly impact dopaminergic neurotransmission, by modulating the function of the dopamine transporter and specifically damaging dopamine-rich regions of the CNS. HIV infection of the CNS has long been associated with dopaminergic dysfunction, but the mechanisms remain undefined. The specific effect(s) of Tat on dopaminergic neurotransmission may be, at least partially, a mechanism by which HIV infection directly or indirectly induces dopaminergic dysfunction. Therefore, precisely defining the specific effects of Tat on the dopaminergic system will help to elucidate the mechanisms by which HIV infection of the CNS induces neuropsychiatric, neurocognitive and neurological disorders that involve dopaminergic neurotransmission. Further, this will provide a discussion of the experiments needed to further these investigations, and may help to identify or develop new therapeutic approaches for the prevention or treatment of these disorders in HIV-infected individuals.

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Increases in CSF dopamine in HIV patients are due to the dopamine transporter 10/10-repeat allele which is more frequent in HIV-infected individuals

Cited by 27 publications

References 40 publications

Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

The role of catecholamines in HIV neuropathogenesis

HIV, Tat and dopamine transmission

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