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Review
. 2014:118:231-313.
doi: 10.1016/B978-0-12-801284-0.00009-9.

Interactions of HIV and drugs of abuse: the importance of glia, neural progenitors, and host genetic factors

Kurt F Hauser  1 , Pamela E Knapp  2
Affiliations
Review

Interactions of HIV and drugs of abuse: the importance of glia, neural progenitors, and host genetic factors

Kurt F Hauser et al. Int Rev Neurobiol. 2014.

Abstract

Considerable insight has been gained into the comorbid, interactive effects of HIV and drug abuse in the brain using experimental models. This review, which considers opiates, methamphetamine, and cocaine, emphasizes the importance of host genetics and glial plasticity in driving the pathogenic neuron remodeling underlying neuro-acquired immunodeficiency syndrome and drug abuse comorbidity. Clinical findings are less concordant than experimental work, and the response of individuals to HIV and to drug abuse can vary tremendously. Host-genetic variability is important in determining viral tropism, neuropathogenesis, drug responses, and addictive behavior. However, genetic differences alone cannot account for individual variability in the brain "connectome." Environment and experience are critical determinants in the evolution of synaptic circuitry throughout life. Neurons and glia both exercise control over determinants of synaptic plasticity that are disrupted by HIV and drug abuse. Perivascular macrophages, microglia, and to a lesser extent astroglia can harbor the infection. Uninfected bystanders, especially astroglia, propagate and amplify inflammatory signals. Drug abuse by itself derails neuronal and glial function, and the outcome of chronic exposure is maladaptive plasticity. The negative consequences of coexposure to HIV and drug abuse are determined by numerous factors including genetics, sex, age, and multidrug exposure. Glia and some neurons are generated throughout life, and their progenitors appear to be targets of HIV and opiates/psychostimulants. The chronic nature of HIV and drug abuse appears to result in sustained alterations in the maturation and fate of neural progenitors, which may affect the balance of glial populations within multiple brain regions.

Keywords: Chemokine (C–C motif) receptor 5 (CCR5); Cocaine; Drug/substance abuse; Gene polymorphisms; Methamphetamine; Neural stem cells; Neurogenesis/gliogenesis; Neuroimmunology; Neuropathology; Neuropharmacology; μ opioid receptor (OPRM1).

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Conflict of interest statement

Conflict of Interest Statement: The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Opiate drugs exacerbate HIV-1 neuropathogenesis through direct actions on glia—especially microglia and astroglia. Microglia are likely infected through interactions with infiltrating, perivascular macrophages, and propagate the bulk of HIV infection in the CNS. HIV-1 also infects astroglia, but to a far lesser extent, and perhaps without production of new virus., Infection results in the production of reactive oxygen and nitrogen species (ROS and RNS, respectively), pro-inflammatory cytokines, and the release of HIV-1 proteins such as gp120 and Tat. All of these promote inflammation and cytotoxicity in bystander neurons and glia. Opiate abuse alone can cause premature Alzheimer-like changes (Anthony et al., 2010) and morphine by itself can enhance neurotoxicity in vitro (Zou et al., 2011); however, opiates appear to potentiate many of the pathophysiological effects of HIV in the central nervous system of infected individuals. Multiple neuronal and glial types express μ-opioid receptors (MOR). Many of the neurodegenerative effects of opioid-HIV interactions are the result of direct actions on microglia and astroglia, which then lead to a positive feedback cycle of inflammatory/cytotoxic signaling between HIV-1-infected microglia and astroglia. Abbreviations: α-chemokine “C-X-C” receptor 4 (CXCR4); altered or changed (Δ); β-chemokine “C-C” receptor 5 (CCR5); blood-brain barrier (BBB); decreased (↓); fractalkine (CX3CL1); fractalkine receptor (CX3CR1); increased (↑); interferon-γ (IFN-γ); interleukin-6 (IL-6); intracellular Ca2+ concentration ([Ca2+]i); intracellular sodium concentration ([Na+]i); monocyte chemoattractant protein-1 (MCP-1 [or CCL2]); peripheral blood mononuclear cells (PBMCs); regulated upon activation, normal T-cell expressed, and secreted (RANTES [or CCL5]); Toll-like receptor (TLR). Fractalkine released by neurons (and astroglia) can be neuroprotective by limiting the neurotoxic actions of microglia (blue “┬”); red arrows suggest pro-inflammatory/cytotoxic interactions. Modified and reprinted from reference (Hauser et al., 2012) an “open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.”
Figure 2
Figure 2
Psychostimulants can increase synaptic damage through direct actions on neurons and glia, including both microglia and astroglia. Psychostimulants block dopamine, serotonin (5HT), and norepinephrine (NE) transport resulting in excessive accumulations of these neurotransmitters in the synaptic cleft. Dopaminergic neurons are particularly vulnerable to methamphetamine, which disrupts dopamine transporter (DAT) and vesicular monoamine transporter 1 (VMAT2) function and can damage presynaptic terminals of neurons. Synaptic injury is accompanied by the production of reactive oxygen (ROS) and nitrogen (RNS) species, and the production of damage-associated molecular patterns (DAMPs) that trigger activation of pattern recognition receptors (PRRs), including Toll-like receptor 9 (TLR9), nucleotide-binding oligomerization domain-like receptors (NLRs) and other PRRs (e.g., receptor for advanced glycation endproducts or RAGE) expressed by microglia and astroglia. Importantly, psychostimulants (especially methamphetamine) appears to activate neurons directly through the disruption of monoaminergic transporters and VMAT2 mentioned above and through the activation of trace amine-associated receptor 1 (TAAR1). Psychostimulants also disrupt glial function directly by increasing intracellular ROS and likely Ca2+ concentrations ([Ca2+]i), NF-κB transcriptional activity, and by activating sigma-1-receptors (sigma-1; red, dashed-line outline), especially in the case of cocaine, and enzyme systems driving oxidative and nitrosative stress especially in microglia (and other cell types). Increases in NF-κB transcriptional activity result in increased microglial, and to a lesser extent astroglial, production of tumor necrosis factor-�� (TNF-α), interferon-γ (IFN-γ), interleukin-1β (IL-1β), and various other cytokines, as well as tissue inhibitor of metalloproteinase-1 (TIMP-1). Psychostimulants also obstruct the buffering of extracellular glutamate by inhibiting excitatory amino acid transporters-1/2 (EAAT1/2) and the conversion of glutamate to glutamine by inhibiting glutamine synthetase, as well as by limiting glucose metabolism in astrocytes. Collectively, neuronal injury and intensified glial activation promotes positive microglial-astroglial, and neuronal-glial feedback that cause spiraling increases in neuroinflammation and neuronal injury. If unrestrained, the cumulative insults result in lasting neurodegenerative changes. Modified and reprinted from reference (Beardsley & Hauser, 2014). Reprinted from Advances in Pharmacology, Vol. 69, Patrick M. Beardsley and Kurt F. Hauser, Chapter One – Glial Modulators as Potential Treatments of Psychostimulant Abuse, 1–69, Copyright 2014, with permission from Elsevier.
Figure 3
Figure 3
Computer-generated model of a MOR-CCR5 dimer (A). The helical portions colored in blue and green represent CCR5, while the red and yellow helices represent MOR (A). Each ribbon was given an arbitrary color in order to distinguish individual helices from one another (A). Representation of the Poisson–Boltzmann electrostatic potentials at the surface of the heterodimer using the APBS plugin by PYMOL (El-Hage et al., 2013) (B). Acidic residues are shown in red (−2 kBT/e); basic residues are shown in blue (+2 kBT/e); white represents uncharged residues (B). The model predicts that a majority of the interactions between the two receptors are hydrophobic (B). Chemical structure of a bivalent ligand that binds both MOR and CCR5 receptors concurrently (C) (for complete description see, El-Hage et al., 2013). Reprinted with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health: AIDS (El-Hage et al.), copyright 2013.
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