Accelerated brain aging with opioid misuse and HIV: New insights on the role of glially derived pro-inflammation mediators and neuronal chloride homeostasis

Abstract

Opioid use disorder (OUD) has become a national crisis and contributes to the spread of human immunodeficiency virus (HIV) infection. Emerging evidence and advances in experimental models, methodology, and our understanding of disease processes at the molecular and cellular levels reveal that opioids per se can directly exacerbate the pathophysiology of neuroHIV. Despite substantial inroads, the impact of OUD on the severity, development, and prognosis of neuroHIV and HIV-associated neurocognitive disorders is not fully understood. In this review, we explore current evidence that OUD and neuroHIV interact to accelerate cognitive deficits and enhance the neurodegenerative changes typically seen with aging, through their effects on neuroinflammation. We suggest new thoughts on the processes that may underlie accelerated brain aging, including dysregulation of neuronal inhibition, and highlight findings suggesting that opioids, through actions at the μ-opioid receptor, interact with HIV in the central nervous system to promote unique structural and functional comorbid deficits not seen in either OUD or neuroHIV alone.

Figure 1.

Opioids can exacerbate HIV-1 CNS pathology through direct actions on phenotypically distinct subpopulations of opioid-receptor expressing glia—especially subsets of μ-opioid receptor- (MOR) expressing microglia and astroglia. The illustration above includes known and likely targets of opioid and HIV interactions. 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 the production of new virus. Infection results in the production of reactive oxygen and nitrogen species, 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. OUD alone can cause premature Alzheimer-like changes and morphine by itself can enhance neurotoxicity in vitro; however, opiates appear to potentiate many of the pathophysiological effects of HIV in the central nervous system of infected individuals. μ, δ and κ-Opioid receptor expression varies among phenotypically distinct subpopulations of astro- and microglia and is quite heterogeneous [98,99]—differing among brain regions, throughout ontogeny, and depending on context; many astro- and microglia subpopulations do not express opioid receptors [–102]. 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, updated, and reprinted from reference [66] an “Open Access” article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.5/).

Figure 2.. Effects of opioid- and/or HIV− induced deficits in KCC2 expression and/or function on neuronal excitability.

Our working model is that KCC2 pumps Cl⁻ out of mature neurons allowing GABA_AR activation to promote Cl⁻ entry and neuronal inhibition. HIV and opioid-induced decreases in KCC2, which increase [Cl⁻]_i result in neuronal depolarizing upon GABA_AR activation and excess excitation in the presence of glutamate agonists (not shown). NKCC1 (which pumps Cl⁻ into neurons) function tends to be constant and unaffected by extracellular factors or opioids and HIV.