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  • Overall while cART has significantly prolonged life

    2021-10-22

    Overall, while cART has significantly prolonged life and ameliorated HIV-associated disease, HIV infection of the CNS still induces a number of cognitive, behavioral and motor symptoms, along with substantial neuropathology. Data show that the inflammatory processes driving neurological disease persist in the individuals using fully suppressive cART (Tavazzi, 2014, Spudich, 2016, Anthony, 2005, Yuan, 2013, Yadav and Collman, 2009, Spudich, 2011), indicating that these processes are mediated by interactions distinct from viral replication. Over time, the damage from this chronic inflammation accumulates, interfering with neurotransmission and dysregulating neuroimmune communication. Many of these issues overlap with neurological issues associated with aging, and the synergy between these problems is growing (Clifford, 2017) as the age of the HIV-infected population increases. Further, the ability to suppress but not eliminate HIV has resulted in an increased focus on the insults initiated by chronic infection and neuroinflammation, and the resultant changes in neurotransmission and CNS homeostasis.
    Catecholamines Catecholamines are monoamines, organic compounds containing a catechol ring (ortho-dihydroxybenzene) linked to an amino side-group. Dopamine, norepinephrine or noradrenaline, and epinephrine or adrenaline are catecholamine neurotransmitters derived from the amino h89 tyrosine. Catecholamines are synthesized in their cognate neurons, both in cell bodies and in the nerve terminals. From there they h89 are rapidly transported and stored in the endoplasmic reticulum or in vesicles along dendrites and at synaptic terminals (Kelly, 1993, Barnes et al., 2015). The release and reuptake of these molecules is highly-regulated through complex mechanisms, which act independently or in conjunction with other regulatory mechanisms. These molecules play vital roles in the modulation of behavior, metabolism, autonomic function, and immunity, acting in both the periphery and the CNS (Marino and Cosentino, 2013). In the CNS, dopamine, norepinephrine, and to a much lesser extent epinephrine enable interneuronal communications that modulate neuronal activity and influence behavior. While the majority of studies on the actions of catecholamines have been performed in neurons, recent studies show that all catecholamines also have immunomodulatory actions. These occur in a number of different immune cell types, including T-cells, myeloid cells and neutrophils, and has been widely reviewed (Gaskill, 2013, Pinoli et al., 2017, Barnes et al., 2015, Bellinger and Lorton, 2014, Scanzano and Cosentino, 2015, Scanzano, 2015, Beaulieu and Gainetdinov, 2011). Although these and many other studies clearly demonstrate an immunoregulatory effect of catecholamine interaction with immune cells, it is important to note that many of them used pharmacologic levels (10−6M and higher) of catecholamines or catecholamine receptor agonists/antagonists. Therefore, it is not entirely clear how human immune cells in the CNS, where catecholaminergic concentrations remain unclear, respond to catecholaminergic stimulation in vivo. Further, during HIV infection, these effects may be changed by HIV-associated disruption in catecholaminergic tone.
    Effects of dopamine on HIV infection Dopamine has long been associated with retroviral infection, as studies almost four decades ago showed dopamine-receptor antagonists such as chlorpromazine and haloperidol have a lytic effect on retroviruses and inhibit reverse transcriptase (Wunderlich and Sydow, 1980, Rohr, 1999). More recently, Rohr and colleagues found pharmacologic dopamine increases HIV replication in Jurkat T-cells and PBMCs by promoting viral transcription through NF-κB (Rohr, 1999, Scheller, 2000), and dopamine also increased HIV production in chronically infected ACH-2 T-cells (Kumar, 2006). Increasing dopamine availability in the CNS of SIV-infected macaques using the MAO-inhibitor selegiline and L-DOPA significantly enhanced CNS viral replication, increased microglial activation, induced vacuole formation and disrupted dendritic architecture (Czub, 2001, Czub, 2004). These studies indicated that dopamine, a neurotransmitter, might contribute to the progression of NeuroHIV by directly increasing infection in immune cells.