HIV, Tat and dopamine transmission

Abstract

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.

HIV-1 Tat Length: Comparative and Functional Considerations

“…Within the central nervous system (CNS), extracellular Tat can recruit peripheral immune cells that has been shown to lead to low levels of chronic inflammation through activation of bystander cells and release of pro-inflammatory cytokines, such as interleukin (IL) 1 beta (IL-1β), IL-6, and monocyte chemoattractant protein 1 (MCP-1) from monocytes and macrophages (Hofman et al, 1994;Albini et al, 1998;Hudson et al, 2000;Pulliam et al, 2007;Rayne et al, 2010a;Bachani et al, 2013). Additionally, Tat has been shown to be directly neurotoxic through hyper-activation of neurons (Fields et al, 2015), which contributes to the development of HIV-1-associated neurocognitive disorders (HAND) (Gaskill et al, 2017). These functional properties, however, are dependent on the amino acid mutations present at a number of different Tat residues.…”

Persistent EcoHIV infection induces nigral degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated mice

“…This brain region exhibits increased susceptibility to neuronal cell death itself, so the presence of virus or viral particles may lead to increased neuronal cell death that has not yet been observed in other regions of the brain (Haddad and Nakamura, 2015; Naoi and Maruyama, 1999). Tat has been implicated in many studies as having a neurotoxic effect on the dopamine transmission system (Gaskill et al , 2017). Tat may directly impact dopaminergic neurotransmission through modulation of the dopamine transporter and dysregulating Ca 2+ needed for baseline activity and cell signaling, or by specifically damaging the areas of the brain that are dopamine-rich, including the substantia nigra and striatum (Gaskill et al , 2017; Hu, 2016; Silvers et al , 2007).…”

“…Tat has been implicated in many studies as having a neurotoxic effect on the dopamine transmission system (Gaskill et al , 2017). Tat may directly impact dopaminergic neurotransmission through modulation of the dopamine transporter and dysregulating Ca 2+ needed for baseline activity and cell signaling, or by specifically damaging the areas of the brain that are dopamine-rich, including the substantia nigra and striatum (Gaskill et al , 2017; Hu, 2016; Silvers et al , 2007). Tat also inhibits the expression of tyrosine hydroxylase (TH), an enzyme needed for dopamine production, ultimately affecting dopamine transmission (Zauli et al , 2000).…”

Two‐pore channels regulate Tat endolysosome escape and Tat‐mediated HIV‐1 LTR transactivation

“…32,33 In brain, secreted Tat is taken up rapidly by CNS cells via endocytosis by interacting with specific cell surface proteins and receptors. [24][25][26][27]34,35 Following its endocytosis and internalization into endolysosomes, Tat must undergo endolysosome escape into the cytosol, where it can transit to the nucleus and activate the HIV-1 LTR promoter. [36][37][38] However, it is not clear how Tat escapes endolysosomes.…”