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Review
. 2020 Jun 24:10:261.
doi: 10.3389/fcimb.2020.00261. eCollection 2020.

The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs

Anna Maria Gorska  1 , Eliseo A Eugenin  1
Affiliations
Review

The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs

Anna Maria Gorska et al. Front Cell Infect Microbiol. .

Abstract

Glutamate (Glu) is the most abundant excitatory neurotransmitter in the central nervous system (CNS). HIV-1 and viral proteins compromise glutamate synaptic transmission, resulting in poor cell-to-cell signaling and bystander toxicity. In this study, we identified that myeloid HIV-1-brain reservoirs survive in Glu and glutamine (Gln) as a major source of energy. Thus, we found a link between synaptic compromise, metabolomics of viral reservoirs, and viral persistence. In the current manuscript we will discuss all these interactions and the potential to achieve eradication and cure using this unique metabolic profile.

Keywords: HIV; NeuroHIV; cure; dementia; glutamate; glutamine; reservoirs.

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Figures

Figure 1
Figure 1
Representation of the uptake and mitochondrial delivery system of glucose, glutamate, and glutamine. Glucose enters the cells by glucose transporter-1 (Glut-1), cystine, Gln, and Glu also are uptake by specific transporters such as cystine/glutamate antiporter (xCT), Na+ and Cl−-dependent neurotransmitter transporter (SLC6A14), and neutral amino acid transporter (SLC1A5), respectively. All proteins affected by HIV-1 infection. Upon uptake, these molecules can become part of the glycolysis, GSH synthesis, or the TCA. In the brain, metabolism of these mediators generates lactate that exits the cells via the monocarboxylete transporter (MCT).
Figure 2
Figure 2
Pathways of Glutamate/GABA synthesis-neuro-glia interaction. The cartoon represents the mutual interaction of astrocyte and glutamate (Glu) and GABA neuron. Glu-GABA cycle enzymes: (1) aminotransferases (AT), (2) glutamine synthetase (GS), (3) glutamate dehydrogenase (GDH)/aspartate aminotransferase (AAT), (4) glutaminase (PAG), (5) glutamate decarboxylase (GAD), (6) GABA transaminase (GABA-T)/succinate-semialdehyde dehydrogenase (SSADH) (Schousboe et al., 2013).
Figure 3
Figure 3
Mechanism of Glu neurotoxicity in NeuroHIV pathogenesis. Glu is a critical neurotransmitter dysregulated in HIV-1 infection and HAND. Imbalance in the Glu/GABA cycle impaired the excitatory/inhibitory state of the neurons resulting in persistent stimulation of NMDARs. The diagram represents the activated state of astrocytes and microglia/macrophages. In the CNS, microglia, macrophages, and a small population of astrocytes become infected and carry HIV-integrated DNA. Although astrocytes cannot produce the virus, they contribute to neurotoxicity mediated by the production of viral proteins that are not blocked by ART and the subsequent secretion into neighboring cells such as neurons and glia. Another source of toxicity is the persistent activation of resident glial cells that increase Glu synthesis and release into the extracellular space.
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