Abstract
The persistence of human immunodeficiency virus-1 (HIV)-associated neurocognitive disorders (HAND) in the era of effective antiretroviral therapy suggests that modern HIV neuropathogenesis is driven, at least in part, by mechanisms distinct from the viral life cycle. Identifying more subtle mechanisms is complicated by frequent comorbidities in HIV+ populations. One of the common confounds is substance abuse, with cannabis being the most frequently used psychoactive substance among people living with HIV. The psychoactive effects of cannabis use can themselves mimic, and perhaps magnify, the cognitive deficits observed in HAND; however, the neuromodulatory and anti-inflammatory properties of cannabinoids may counter HIV-induced excitotoxicity and neuroinflammation. Here, we review our understanding of the cross talk between HIV and cannabinoids in the central nervous system by exploring both clinical observations and evidence from preclinical in vivo and in vitro models. Additionally, we comment on recent advances in human, multi-cell in vitro systems that allow for more translatable, mechanistic studies of the relationship between cannabinoid pharmacology and this uniquely human virus.
Highlights
There are an estimated 38 million people living with human immunodeficiency virus-1 (HIV) globally, of which only 81% are likely aware of their HIV status and only 67% are being treated with antiretroviral therapy (ART) [1]
Global efforts continue to focus on preventing new infections and reducing viral transmission with effective ART, yet there remains an immense burden of care, not for viral control, and for treating the long-term consequences of infection and treatment, including immune system dysfunction, gastrointestinal damage and anorexia, neuropathic pain, and HIV-associated neurocognitive disorders (HAND)
HAND is a descriptor for a number of mood, memory and learning, cognitive, and motor disorders associated with central nervous system (CNS) damage following HIV infection
Summary
HIV is thought to enter the brain either as a free virion or via infiltration of infected peripheral cells that traverse the blood–brain barrier (BBB) into the parenchyma of the central nervous system (CNS). Evidence that HIV-infected monocytes can cross the blood–brain barrier, as reviewed by Williams et al, suggests that peripheral monocytes and their differentiated macrophages may contribute to the establishment of the CNS viral reservoir [20]. Immunohistochemical studies have identified HIV protein, DNA, and RNA in brain-resident macrophages, microglia [21], and astrocytes [22]; neurons and oligodendrocytes are not infected. HIV damages the BBB, allowing for inappropriate ingress of peripheral cells and opportunistic microbes, creating a feed-forward loop of HIV infiltration and inflammation. These sequelae of HIV infiltration into the CNS were originally characterized in the context of pre-ART encephalitis. Cannabinoids target receptors integral to the regulation of both excitatory neuronal signaling and inflammation, providing an opportunity for cross talk between the most robust neurotoxic consequences of HIV infection and the most commonly used DoA in HIV+ populations
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