Immunomodulatory Properties of Kappa Opioids and Synthetic Cannabinoids in HIV-1 Neuropathogenesis

Abstract

Anti-retroviral therapy (ART) has had a tremendous impact on the clinical outcomes of HIV-1 infected individuals. While ART has produced many tangible benefits, chronic, long-term consequences of HIV infection have grown in importance. HIV-1-associated neurocognitive disorder (HAND) represents a collection of neurological syndromes that have a wide range of functional cognitive impairments. HAND remains a serious threat to AIDS patients, and there currently remains no specific therapy for the neurological manifestations of HIV-1. Based upon work in other models of neuroinflammation, kappa opioid receptors (KOR) and synthetic cannabinoids have emerged as having neuroprotective properties and the ability to dampen pro-inflammatory responses of glial cells; properties that may have a positive influence in HIV-1 neuropathogenesis. The ability of KOR ligands to inhibit HIV-1 production in human microglial cells and CD4 T lymphocytes, demonstrate neuroprotection, and dampen chemokine production in astrocytes provides encouraging data to suggest that KOR ligands may emerge as potential therapeutic agents in HIV neuropathogenesis. Based upon findings that synthetic cannabinoids inhibit HIV-1 expression in human microglia and suppress production of inflammatory mediators such as nitric oxide (NO) in human astrocytes, as well as a substantial literature demonstrating neuroprotective properties of cannabinoids in other systems, synthetic cannabinoids have also emerged as potential therapeutic agents in HIV neuropathogenesis. This review focuses on these two classes of compounds and describes the immunomodulatory and neuroprotective properties attributed to each in the context of HIV neuropathogenesis.

Opioids and Viral Infections: A Double-Edged Sword

“…Opioid systems affect viral replication and pathogenesis in several ways (Figure 2 ). Interestingly, opioids have either a beneficial or deleterious effect on the pathogenesis of viruses directly through central nervous system (CNS) by their intrinsic immunomodulatory actions (Hu et al, 2011 ). Depending on the virus type, activation of opioid receptors in immune and immune-associated cells directly or indirectly enhances (Wang C.-Q.…”

“… Opioid systems effects on viral replication and pathogenesis . Opioids may positively or negatively affect the pathogenesis of viruses directly through the central nervous system (Hu et al, 2011 ). Opioid receptors activation in immune and immune-associated cells directly or indirectly affect viral pathogenesis via modulating host immune responses (Salimi et al, 2013 ).…”

Cannabinoid Type-2 Receptor Agonist, JWH133 May Be a Possible Candidate for Targeting Infection, Inflammation, and Immunity in COVID-19

“…CB2R has also been shown to be involved in HIV-associated neuropathogenesis by enhancing migration and altering the expression and compartmentation of the β-chemokine receptor CCR-3, as well as releasing inflammatory factors, including the virus-specified trans-activating protein Tat, which further elicits chemokines, cytokines, and a chemotactic response from microglia [130]. Numerous studies have shown that activation of CB2R exerts pleiotropic effects by ameliorating neuroinflammation via inhibiting replication of HIV-1, reducing microglia migration towards HIV-1 Tat, rescuing neurons and endothelial cells, and suppressing viral infection, as well as associated inflammatory responses [131][132][133][134]. CB2R ligands have been shown to suppress replication of HIV-1, rather than interfering with viral entry in microglia [131].…”

Opioid and neuroHIV Comorbidity – Current and Future Perspectives

“…Despite some reports of morphine triggering immune activation via Toll-like receptor 4 (TLR4) (Terashvili et al 2008 ; Hutchinson et al 2010 ; Coller and Hutchinson 2012 ; Hutchinson et al 2012 ; Theberge et al 2013 ; Lacagnina et al 2017 ) by binding to a myeloid differentiation protein-2 intermediary (Wang et al 2012 ), this is contrary to the typical actions of opiates, which by themselves (and in the absence of a priming event such as HIV co-exposure) tend to suppress immune function (Eisenstein 2019 ). A vast majority of the immune, antinociceptive, and other physiological effects of opioids are mediated by opioid receptors per se and not TLR4 (Hu et al 2011 ; Fukagawa et al 2013 ; Stevens et al 2013 ; Mattioli et al 2014 ; Eisenstein 2019 ).…”