The Effects of Opioids on HIV Neuropathogenesis

Abstract

HIV associated neurocognitive disorders (HAND) are a group of neurological deficits that affect approximately half of people living with HIV (PLWH) despite effective antiretroviral therapy (ART). There are currently no reliable molecular biomarkers or treatments for HAND. Given the national opioid epidemic, as well as illegal and prescription use of opioid drugs among PLWH, it is critical to characterize the molecular interactions between HIV and opioids in cells of the CNS. It is also important to study the role of opioid substitution therapies in the context of HIV and CNS damage in vitro and in vivo. A major mechanism contributing to HIV neuropathogenesis is chronic, low-level inflammation in the CNS. HIV enters the brain within 4–8 days after peripheral infection and establishes CNS reservoirs, even in the context of ART, that are difficult to identify and eliminate. Infected cells, including monocytes, macrophages, and microglia, produce chemokines, cytokines, neurotoxic mediators, and viral proteins that contribute to chronic inflammation and ongoing neuronal damage. Opioids have been shown to impact these immune cells through a variety of molecular mechanisms, including opioid receptor binding and cross desensitization with chemokine receptors. The effects of opioid use on cognitive outcomes in individuals with HAND in clinical studies is variable, and thus multiple biological mechanisms are likely to contribute to the complex relationship between opioids and HIV in the CNS. In this review, we will examine what is known about both HIV and opioid mediated neuropathogenesis, and discuss key molecular processes that may be impacted by HIV and opioids in the context of neuroinflammation and CNS damage. We will also assess what is known about the effects of ART on these processes, and highlight areas of study that should be addressed in the context of ART.

Morphine exposure exacerbates HIV-1 Tat driven changes to neuroinflammatory factors in cultured astrocytes

“…HIV-1 Tat also contains a cysteine-rich domain containing highly conserved cysteine residues that are critical for disulfide-bond formation (amino acids [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. We also observed a loss of suppression of β-catenin activity by a C31R Tat mutant in the presence or absence of morphine (Fig 4B and 4C).…”

“…Current estimates of opiate use disorder diagnoses in the United States number near two million, suggesting a significant reciprocal risk between individuals that abuse drugs intravenously and HIV-1 infection rates [30]. Neurocognitive deficits associated with long-term HIV-1 infection can be exacerbated with opiate abuse due to detrimental effects on immune cells.…”

“…The mu opioid receptor is the most common target of opiates and is expressed on many different cell types; morphine, a derivative of heroin, binds to this receptor at a very high affinity. The effects of Tat and morphine on cells of the CNS have been explored extensively in vitro and in vivo, and phenotypes observed could correlate with symptoms of neurodegeneration [30]. For example, in vitro expression of Tat, exposure to morphine, or both has been demonstrated to decrease fidelity of the BBB and subsequently increase immune cells transmigration across the barrier in vitro [74].…”

“…In addition to cytotoxic effects due to direct infection with HIV-1, the CNS represents an environment where secreted viral proteins, cytokines, chemokines, and small molecules can all contribute to neurotoxicity [4,[27][28][29][30][31]. Therefore, proximity to HIV-1 infected cells can result in cell and tissue damage.…”

Opioid Use Disorders in People Living with HIV/AIDS: A Review of Implications for Patient Outcomes, Drug Interactions, and Neurocognitive Disorders

“…As previously noted, there is a relatively high co-incidence of PLWHA who either use or abuse opioids. In the brain, the primary targets of HIV include monocytes, macrophages, and microglia [ 71 ]. HIV enters the CNS as early as 8 days after infection via HIV-infected monocytes and spreads the infection in the CNS cells, especially in perivascular macrophages and microglia [ 72 , 73 , 74 ].…”