Important role of microglia in HIV-1 associated neurocognitive disorders and the molecular pathways implicated in its pathogenesis

Figures & data

Table 1. The role of viral regulatory proteins in HAND.

Viral gene	HIV proteins	Localization	Action	Mechanism of action	References
Structural	gp120	Membrane of infected cells (envelop protein)	Direct and indirect damage	Meddles in N-methyl-D-aspartate receptor; produces oxidative stress; provokes activation of macrophages, microglia and astrocytes; induces release of cytokines and blocks glutamate uptake	Galicia et al. 2002; Nath 2002; Chen et al. 2011; Kovalevich and Langford 2012; Zhou and Saksena 2013; Ivanov et al. 2016; Scutari et al. 2017
Structural	gp41	Membrane of infected cells (envelop protein)	Direct and indirect damage	Induces cytokines and produces nitric oxide by iNOS	Nath 2002; Kovalevich and Langford 2012; Mastrantonio et al. 2016
Regulatory	Nef	Surface of infected cells	Direct damage	Inhibits K channels	Nath 2002; Mangino et al. 2015; Scutari et al. 2017
Regulatory	Tat	Secreted into extracellular medium	Direct and indirect damage	Enhances intracellular calcium; produces reactive oxygen intermediates; actives cells of inmune system; induces release of cytokines and chemokines and directs excitation of neurons	Haughey et al. 2001; Galicia et al. 2002; Nath 2002; Kanmogne et al. 2005; Ivanov et al. 2016; Scutari et al. 2017
Regulatory	Vpr	CSF of HAND patients	Direct damage	Forms ion channels across cell membrane	Galicia et al. 2002; Nath 2002; Kanmogne et al. 2005 Ivanov et al. 2016; Scutari et al. 2017
Regulatory	Vpu	Unknown	Direct damage	Increases ion channel activity	Eckstein et al. 2001; Nath 2002; Varthakavi et al. 2003; Hsu et al. 2004; Kovalevich and Langford 2012

Figure 1. Schematic representation of mechanisms of HIV neurotoxicity. The Gp41, Gp120, Tat, Vpr, Vpu and Nef viral proteins, that circulate in the blood produce enhanced ROS production, results in alteration of BBB. Different process occurs during the neurotoxicity like enhanced oxidation of DNA nucleic bases, genomic instability, aggregation of ceramide, stimulation of A-type transient outward K + currents by Kv channels, and production of proinflammatory cytokines.

Table 2. Typification by cognitive impairment and recommendations for Monitoring Patients With HAND.

Stage of HAND	Neurocognitive impairment and functional status	Clinical recommendations	References
ANI	Involves two cognitive domains that do not interfere with everyday function	Monitored initially at six months and re-evaluated at month twelve	(Bouwman et al. 1998; Antinori et al. 2007; Mind Exchange Working Group 2013; Scutari et al. 2017)
MND	Involves, at least, two cognitive domains that produce, at least, mild interference in daily function	Monitored clinically initially at months three and six, then semi-annually until a plateau of response have been observed	(Antinori et al. 2007; Cysique et al. 2009; Heaton et al. 2011; Mind Exchange Working Group 2013; Scutari et al. 2017)
HAD	Involves, at least, two cognitive domains that substantially interferes with daily functioning	Periodically reassessed, perhaps as frequently as monthly if practical	(Cysique et al. 2006; Antinori et al. 2007; Heaton et al. 2011; Mind Exchange Working Group 2013; Scutari et al. 2017)

Figure 2. Schematic representation of the effects of HIV and its viral proteins on the cells of the CNS of HAND patients. HIV enters into the brain, especially perivascular space (the main site for viral replication), within infected macrophages or as free virions or viral particles. HIV infects and activates macrophages, astrocytes and microglia in the perivascular space, the main site for viral replication. Macrophages, and astrocytes and activated microglia contribute to the release of proinflammatory cytokines and chemokines, which provoke additional influx of immune cells and mediate neuronal damage. Conversely, some inflammatory mediators can also promote neuronal survival. HIV induces activated astrocytes which secrete proinflammatory cytokines, chemokines and glutamate. Together with viral proteins and HIV-induced chemokines, these substances overstimulate NMDA receptors, causing excitotoxicity. All the events caused by HIV proteins, excitotoxicity, and inflammation lead to axonal injury and neuronal apoptosis.

Figure 3. “Shock and kill” strategy involves activating viral replication to eliminate reservoirs and to target latently-infected cells. LRAs have an important role in the reactivate transcription for the “shock”. LRAs promote chromatin decompaction and ARN pol II recruitment to induce virus transcription. ART is maintained during this phase to clear reservoir without virus propagation in other cells. The “kill” can be enhanced by stimulation of the cell-mediated immune response or by using neutralising and/or engineered antibodies. The “block and lock” strategy relates on the induction of a state of deep-latency to prevent HIV-1 transcription. LPA inhibit various step of virus replication, transcription by Tat inhibition and RNA export. One promising LPA is a miRNA which inhibit virus expression.