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EDITORIAL REVIEW

Cannabinoids and inflammation

implications for people living with HIV

Costiniuk, Cecilia T.a,b,c,d; Jenabian, Mohammad-Alid,e,f

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doi: 10.1097/QAD.0000000000002345
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Abstract

Introduction

Historically, cannabis was used by people living with HIV (PLWH) to alleviate nausea, vomiting, pain, wasting and anorexia [1,2]. Since the advent of combined antiretroviral therapy (ART), PLWH no longer suffer from anorexia and wasting syndrome, and prolonged nausea and vomiting because of ART is rare. In the modern ART era, preventing and managing common comorbidities seen in the general population, such as cardiovascular disease, diabetes and non-AIDS associated cancers, is a key priority [3,4]. HIV itself appears to be a risk factor for these comorbidities and appears to interact with traditional risk factors [5]. Chronic HIV infection is associated with a state of persistent systemic immune activation, which is thought to be a primary driver for many comorbidities such as atherosclerosis and liver fibrosis, in PLWH [6].

Although cannabis has a long history of being used for therapeutic purposes, its anti-inflammatory and immunomodulatory properties make it especially fascinating in the context of chronic HIV infection. Although cannabis use remains common among PLWH in the modern ART era for alleviating symptoms of anxiety and depression and for recreational reasons [2,7], its effects on the immune system in the context of chronic HIV infection merit close attention. Herein, we review the data pertaining to the anti-inflammatory and immunomodulatory effect of cannabis and cannabinoid-based medicines in PLWH.

HIV infection as a chronic inflammatory disease

For the past 25 years, the majority of research on HIV has focused on inhibiting HIV replication. Most people living with HIV (PLWH) can achieve plasma viral load levels below the level of detection within 3 months of ART initiation [8]. Modern antiretrovirals are now very well tolerated by the majority of PLWH and many individuals can now expect to live near-normal life expectancies [9,10]. However, PLWH suffer from a burden of chronic diseases that exceeds the burden found in the general population. Leading comorbidities of PLWH on suppressive ART including cardiovascular disease, metabolic disorders, such as dyslipidemia in addition to malignancies, notably lung and colon cancers [3,4,11–13]. It is thought that low-level HIV replication (below that detected by conventional clinical viral load assays) and chronic systemic inflammation are contributing to the high prevalence of comorbidities [6,14].

The gut is a key player in HIV pathogenesis, as 60–80% of the body's CD4+ T cells are found in the gut, and there is cross-talk between intestinal microbiome, epithelial cells and immune cells [15–17]. During HIV infection, there is massive loss of CD4+ T cells leading to enteropathy and increased gut mucosal permeability, which results in translocation of microbial products from the gut into the periphery and consequently systemic immune activation [6,14,18] Microbial translocation results in stimulation of immune target cells and the release of pro-inflammatory cytokines and consequently systemic immune activation, lymphoid tissue fibrosis and T-cell and B-cell dysfunction [6,18,19]. Following ART initiation, HIV RNA significantly decreases and CD4+ T cells gradually recover, although in some persons this CD4+ T-cell recovery is incomplete. In contrast, recovery of CD4+ T cells in the gastrointestinal tract and lymphoid tissues lags behind the recovery in peripheral blood [15]. Immune activation decreases after ART but in most patients remains significantly increased compared with healthy controls [8]. Chronic immune activation and systemic inflammation lead, in turn, to non-AIDS morbidity and mortality in PLWH [6,18,19].

The endocannabinoid system and cannabinoids

The endocannabinoid system is constituted of endogenous cannabinoids (’endocannabinoids’), cannabinoid receptors, which induce or inhibit signal transduction pathways upon activation, in addition to enzymes, which synthesize or degrade cannabinoids (Table 1) [20–34]. CB1 and CB2 are G-protein-coupled receptors. CB1 receptors are expressed predominantly in the central nervous system but are also found in the lung, gastrointestinal tract, liver and kidneys [35,36]. Their presence in the central nervous system accounts for the psychoactive effects of cannabis [37,38]. High densities of CB1 receptors are located in the basal ganglia, substantia nigra, globus pallidus, cerebellum and hippocampus, but not in the brainstem where breathing is controlled, accounting for the low risk of overdose and toxicity [39]. Within the nervous system, CB1 regulates release of both excitatory and inhibitor neurotransmitters. As CB1 activation reduces excessive glutamate release, this prevents damage from overexcitation [40]. Within the gastrointestinal tract, CB1 activation on enteric neurons is the main mechanism by which cannabinoids affect gut motility, through inhibition of acetylcholine release which in turn reduces smooth muscle contractility and peristalsis [41,42]. In contrast, CB2 receptors are abundant on immune cells including T and B lymphocytes, natural killer cells, monocytes and neutrophils as well as the liver [35,37]. CB2 receptor activation induces apoptosis, inhibits pro-inflammatory cytokine expression, and induces a shift from a Th1 to Th2 immune response and induced myeloid-derived suppressor and T-regulatory cells [43].

Table 1
Table 1:
The endocannabinoid system.

There are many endogenous cannabinoids, or endocannabinoids, with the most studied endocannabinoids outlined in Table 1. Other endocannabinoids including N-palmitoyl ethanolamide (PEA) and oleoylethanolamine (OAE) have also been investigated [44]. Endocannabinoids exert many physiological effects similar to corticosteroids, such as reducing inflammation and inducing euphoria. CB1 receptors are the main targets for the endogenous cannabinoid, anandamide. Anandamide is attributed with inducing a sense of euphoria, as found in the ‘runner's high’ [35,36]. The other principal endocannabinoid is 2-arachidonoylglycerol (2-AG), which functions at both CB1 and CB2 receptors and is found in higher concentrations in the central nervous system than anadamide [35,36]. Neurons can produce endocannabinoids, but unlike most neurotransmitters they are released from cell bodies and not axons [45]. Furthermore, endocannabinoids can impede the release of neurotransmitters into the synapse [40].

The endocannabinoid system plays a role in regulation of a wide spectrum of processes including cognition, pain/sensation, mood, memory, locomotor activity, motivation and others [35,36]. Moreover, the endocannabinoid system is important for normal physiological functions of the gastrointestinal track, such as motility, hunger signaling, gut permeability and inflammation [25]. Of special relevance to PLWH, the endocannabinoid system has been shown to regulate epithelial barrier permeability through its interactions with the gut microbiota [25]. Activation of CB1 receptors in mice increased levels of lipopolysaccharide (LPS), the endotoxin produced by Gram-negative bacteria, via a pathway that decreases expression of tight junction proteins, occludin and zona occudens-1 [46]. Therefore, manipulation of the CB1 receptors receptor can affect gut permeability [25,46]. Furthermore, CB1 and CB2 receptor activation has been shown to ameliorate intestinal inflammation in multiple models of murine colitis [47].

With regards to varieties of cannabis plants, numerous chemovars or chemical varieties of cannabis plants exist [48]. The best described phytocannabinoids with medicinal properties include Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Δ9-THC is a partial agonist at both CB1 and CB2 receptors and is usually the cause for the psychotropic effects of cannabis [37,38]. CBD is thought to mediate its effects through a variety of signalling mechanisms and act as a negative allosteric modulator at CB1[37,38]. CBD has the ability to enhance adenosine signalling (A2A receptor) through inhibition of uptake and provide a noncannabinoid receptor mechanism by which CBD can decrease inflammation [37,38]. An ‘entourage effect’ has been described, whereby a variety of metabolites thought to be inactive significantly increase the activity of the primary endogenous endocannabinoids, anandamide and 2-arachidonoylglycerol [24,49]. The entourage effect has been put forth as an explanation for the more robust performance of botanicals than their components in isolation [49,50]. Examples of phytocannabinoids which have exhibited therapeutic benefits include tetrahydrocannabivarin, cannabigerol and cannabichromene [51]. Terpenoids, which give cannabis plants their flavour and smell, also contribute to the entourage effect. Therefore, ‘minor cannabinoids’ other than Δ9-THC and CBD and cannabis terpenoids are likely to contribute to the overall medicinal effect of plants [49]. Several examples of cannabinoid synergy have previously been described [49]. Synthetic cannabinoids also exist, namely dronabinol (Marinol), which is most often used to control symptoms of chemotherapy-induced nausea and vomiting in cancer [49].

Cannabinoids and inflammation

A major underlying reason for the interest in cannabinoids as medicinal agents relate to their immunomodulatory properties (Table 2) [52–76]. As reviewed by Chiurchiu et al., endocannabinoids 2-arachidonyl glycerol (2-AG) and N-arachidonoylethanolamine or (AEA) have an effect on cells involved in both the innate and adaptive immune responses [33]. Early in-vitro studies demonstrated that Δ9-THC inhibits murine T-cell proliferation and macrophage propagation [77–80]. Stimulated cultured murine splenocytes exposed to varying concentrations of Δ9-THC demonstrated a dose-responsive suppressive effect of Δ9-THC on CD8+ T-cell proliferation and cytolytic activity [77–80]. Furthermore, Δ9-THC decreases T-cell proliferation by inhibition of interleukin (IL)-2 production and stimulation of cAMP immunosuppressive pathway [81,82]. Turning to cytokine-mediated polarization of T cells, several laboratories have shown that Δ9-THC polarizes the immune response towards a Th2 phenotype [83], facilitating immune responses against helminths and other extracellular parasites. Indeed, switch from Th1 to Th2 by Δ9-THC treatment is associated with histone modification signals to Th2 cytokine-related genes and suppressive modification signals to Th1 cytokine genes [84]. Δ9-THC can potently suppress the antitumor immune response, leading to enhanced tumor growth in vivo[85]. Nonnecrotic tumors and spleens were isolated from 3LL tumor-bearing C57BL/6 mice and evaluated for IL-10, transforming growth factor (TGF)-β, and interferon (IFN)-γ production in tumor homogenates and splenocyte culture supernatants. Tumor homogenates and splenocyte supernatants from Δ9-THC-treated mice contained significantly more IL-10 and TGF-β, but less IFN-γ than controls treated with diluent [85,86].

Table 2
Table 2:
Cannabinoid effects on human immune responses.

With regards to CBD, numerous studies have confirmed its anti-inflammatory effects [87,88]. In a murine model of LPS-induced acute lung injury, CBD was shown to reduce inflammation in acute lung injury [89,90]. It was also shown to reduce TNF-α and IFN-γ levels in murine collagen-induced arthritis [91]. In in-vitro cultured astrocytes, CBD diminished β-amyloid-induced neuroinflammation whereas in a mouse model of Alzheimer's disease, it reduced inducible nitric oxide synthase and IL-1β expression [92,93]. In murine models of experimental colitis, CBD reduced colon injury inducible nitric oxide synthase expression, interleukin-1β and interleukin-10 production [94]. When combined together, Δ9-THC and CBD display synergistic anti-inflammatory effects. In a mouse model of Alzheimer's disease, reduced astrogliosis, microgliosis and inflammatory-related molecules in treated AβPP/PS1 mice were more marked after treatment with Δ9-THC and CBD combined than with either Δ9-THC or CBD independently [95]. However, the interactions between cannabinoids are complex and have not been fully elucidated [96].

In human studies, discrepancies have been found compared to animal studies because of usage of much higher doses of cannabinoids in animal vs. human studies and extensive first-pass metabolism for both Δ9-THC and CBD following oral administration [97,98]. Zgair et al.[99,100] showed that oral co-administration of CBD and Δ9-THC with long-chain triglycerides (as would be contained in a high-fat meal) can augment intestinal lymphatic transport and markedly increase systemic bioavailability of cannabinoids in rats [97]. In addition, high concentrations of cannabinoids within the intestinal lymphatic system have previously been reported for compounds, which are absorbed following oral administration into systemic circulation primarily through the intestinal lymphatic system [97,99]. Consequently, Zgair et al.[97] orally administered CBD and Δ9-THC with lipids to rats and found that they could obtain concentrations sufficiently high in the intestinal lymphatic system to induce immunomodulatory effects. Interestingly, the distribution of CBD and Δ9-THC to lymphoid tissues in the intestinal lymphatic system and mesenteric lymph nodes was much higher than the distribution to the spleen, which is the largest lymphatic tissue [97]. Using human peripheral blood mononuclear cells (PBMCs), they showed that cells from multiple sclerosis patients were more susceptible to the immunosuppressive effects of cannabinoids [97]. These investigators also demonstrated that oral administration of CBD and Δ9-THC in humans with lipids can result in significant increases in intestinal lymphatic transport similar to what has been obtained for rats in this study [97,101].

Anti-inflammatory effects of cannabis in the context of HIV/simian immunodeficiency virus infection

Given that chronic HIV infection is associated with a state of persistent immune activation, the effects of cannabis in the context of HIV and SIV infection have been explored in vitro, as well as during animal and human studies (Table 3) [102–130].

Table 3
Table 3:
Role of cannabinoids in HIV infection.
Table 3
Table 3:
(Continued) Role of cannabinoids in HIV infection.

In-vitro studies assessing the impact of cannabinoids during HIV infection

CB1 and CB2 and HIV-1 co-receptors CCR5 and CXCR4 all signal via the Gαi-coupled pathways, sparking interest in exploring the effect of drugs targeting cannabinoid receptors on chemokine co-receptor function and HIV-1 infectivity [102]. In primary CD4+ T cells, agonism at CB2, but not CB1, decreased infection with CXCR4-tropic virus after cell-free and cell-to-cell viral transmission [102]. Furthermore, agonism at CB2 reduced F-actin levels, altering cytoskeleton architecture of resting CD4+ T cells [102]. In another study, change in CB2 expression in relation to HIV-1 infection was evaluated during the process of in-vitro monocyte differentiation into macrophage [103]. Gene and protein expression profiles of CB2 in primary human monocytes were studied. PBMCs from six healthy donors were used within 24 h or allowed to differentiate into macrophages for 7 days by adhesion and exposure to monocyte-granulocyte stimulating factor (M-GSF). Differentiated monocyte-derived macrophages (MDMs) were either examined uninfected or infected with macrophage tropic HIV-1ADA for 7 days. There was a step-wise increase in CB2 expression from monocytes to MDMs to HIV-1-infected MDMs [103]. The team also exposed the HIV-infected MDMs to CB2 receptor agonist JWH133 and found a dose-dependent decrease of reverse transcriptase activity [103]. Administration of the CB2 inverse-agonist/antagonist SR144528 had no significant effect on reverse transcriptase activity; however, when co-administered with JWH133, it counteracted agonist effects completely [103].

Given the proposed association between HIV-associated dementia and a reduced blood–brain barrier (BBB) function, the ability of cannabinoid agonists to restore integrity of human brain microvascular endothelial cells and the BBB following damage because of HIV-1 Gp120 has been examined [104]. Cannabinoid agonists inhibited HIV-1 Gp120-induced calcium influx mediated by substance P and greatly reduced permeability of human brain microvascular endothelial cells [104]. Cannabinoid agonists also prevented tight junction protein down-regulation of zona occludins protein-1, claudin-5, and junctional adhesion molecule-1 in human brain microvascular endothelial cells [104]. Furthermore, cannabinoid agonists inhibited the transmigration of human monocytes across the BBB and blocked the BBB permeability in vivo[104]. In another study involving CD4+ T cells and microglial cell cultures, WIN 55,212-2, a synthetic cannabinoid, was found to inhibit HIV-1 expression in a concentration-dependent and time-dependent manner [105]. This was in contrast to morphine, whereby HIV-1 expression was influenced by the timing of morphine exposure the time of drug exposure [105].

Animal model studies on the role of cannabinoids during HIV/simian immunodeficiency virus infection

Building on data from their in-vitro studies, Chen et al.[106] used a murine model to determine whether Δ9-THC produced similar effects in vivo as had been observed during in-vitro studies. A gp120-expressing plasmid, pVRCgp120, or a vector plasmid, pVRC2000, was injected intramuscularly into mice which were also dosed with Δ9-THC orally [106]. The gp120-specific IFN-γ and IL-2 responses were detected when splenocytes were re-stimulated with a gp120-derived peptide [106]. pVRCgp120 stimulation followed by peptide re-stimulation led to a rise in activation markers CD69+, CD80+, and major histocompatibility complex II [106]. Furthermore, Δ9-THC augmented the IFN-γ response and cellular activation C57Bl/6 wild type mice, but Δ9-THC either suppressed or did not have any effect on CB1 and CB2 knockout (CB1−/−CB2−/−) mice [106]. Therefore, Δ9-THC enhanced HIV antigen-specific immune responses, which occurred through CB1/CB2-dependent and independent mechanisms [106]. In another study, murine perinatal exposure to Δ9-THC on immune function was examined [107]. Murine fetal thymuses express high levels of CB1 and CB2 receptors [107]. Perinatal Δ9-THC exposure resulted in reduced thymic cellularity on gestational days 16, 17, and 18 and postgestational day 1, in addition to significant changes in T-cell subpopulations [107]. These changes were reversed by CB1 and CB2 antagonists [107]. Of note, Δ9-THC perinatal exposure resulted in impact on immune responses in murine life, with peripheral T cells from such mice having subdued proliferative responses to T-cell mitogens and lowered T-cell and antibody responses to HIV-1p17/p24/gp120 [107].

In order to examine the effect of chronic Δ9-THC administration on SIV disease progression, Molina et al.[108] administered Δ9-THC (0.32 mg/kg intramuscularly twice daily) to Indian-derived male rhesus macaques, beginning 28 days prior to infection with SIVmac251. They demonstrated that Δ9-THC administration decreased mortality because of SIV over 11 months and reduced plasma and cerebrospinal fluid SIV viral load [108]. Interestingly, a subsequent study by the same group did not find these protective effects in Indian-derived female rhesus macaques, suggesting a possible drug–sex steroid interaction and highlighting the need for further studies focusing on sex-specific cannabinoid effects on SIV disease [131]. It has been postulated that attenuation of localized tissue inflammatory responses and viral replication in male macaques could have accounted for the protective effects [108].

In another study, which involved Chinese rhesus male macaques, the effects of chronic Δ9-THC administration was examined in four groups of macaques (Δ9-THC+SIV+, Δ9-THC+SIV−, placebo/SIV+ and placebo/SIV− (n = 4/group) [109]. Twice daily Δ9-THC injections for 428 days did not change viral loads, CD4+ counts, CD4+/CD8+ ratios, T-cell proliferation, survival rate and clinical signs of disease progression over time compared with those macaques, which received placebo injections [109]. Moreover, regardless of Δ9-THC administration, all SIV-infected macaques displayed significant decline in CD4+/CD8+ T-cell ratios, loss of CD4+ T cells and increased levels of persistent Ki67+CD8+ T-cell proliferation vs. uninfected animals [109]. In addition, chronic Δ9-THC administration increased B-cell frequency, especially after 3 months, regardless of SIV infection status [109]. The main biological effect of Δ9-THC seen in this study was down-regulation of circulating IgE+ B cells in vivo, which the authors postulate could be mediated via a CB2-related mechanism [109].

The gut is known to harbor the majority of the body's total CD4+ T cells, which are HIV's primary target cells [15–17]. In another study by Kumar et al. involving Indian-origin rhesus macaques, animals were treated for 17 months with Δ9-THC (0.18–0.25 mg/kg intramuscularly twice daily) vs. vehicle administration for 17 months [110]. Duodenal tissues were examined from the macaques about 5 months after infection with SIVmac251. There were lower SIV RNA viral loads in plasma, PBMCs and duodenal tissue in the Δ9-THC-treated vs. vehicle-treated macaques, though differences between HIV proviral DNA between groups did not statistically differ [110]. Elevated duodenal integrin β7+CD4+ and CD8+ central memory T cells and preferential Th2 cytokine levels were also noted between Δ9-THC-treated vs. control groups [110]. Gene array analysis identified six genes important for apoptosis, cell survival, proliferation and morphogenesis and energy and substrate metabolic processesthat were increased in the Δ9-THC-treated vs. control groups [110]. Immunohistochemical staining showed attenuated apoptosis in epithelial crypt cells of THC-treated macaques [110]. The same group also investigated cannabinoids including Δ9-THC on microRNA (miRNA) expression in the gut. Compared with Indian-origin rhesus macaques administered vehicle/SIV, Δ9-THC administration to SIV-infected animals resulted in the selective upregulation of a cluster of the six miRNAs previously shown to have anti-inflammatory effects [111]. They characterized the functional relevance of miR-99b and found its expression increased in SIV-infected macaques [111]. The same group then studied miRNA expression sequentially in intestinal lamia propria leukocytes of eight Indian origin rhesus macaques before and at 21, 90 and 180 days postinoculation with SIV [112]. They demonstrated miR-150 downregulation during T-cell activation, disrupting IL-1 receptor kinase 1 translational control, fostering persistent gastrointestinal inflammation [112].

As epithelial barrier function is epigenetically regulated by inflammation-induced microRNAs [132], Kumar et al.[113] examined the epigenetic regulation of miRNAs when colonic tissue from SIV-infected Indian-origin rhesus macaques was treated ex vivo with Δ9-THC. They found that dysregulated miR-130a and miR-212 expression in colonic epithelium increased epithelial barrier disturbance via modulation of peroxisome proliferator-activated receptor gamma (PPARγ) and occludin expression [113]. Δ9-THC treatment of colonic tissue was able to recover transepithelial electrical resistance (TEER) levels to that observed in control's miRNA mimics [113]. PPARγ mRNA expression was increased when colonic tissue was treated with Δ9-THC, showcasing the therapeutic potential of cannabinoids to restore gut epithelial barrier integrity [113]. Yet another study demonstrated that 10 miRNAs were significantly upregulated in Δ9-THC-treated SIV-infected macaques vs. vehicle-treated SIV-infected macaques. Among these, miR-204 was confirmed to directly target matrix metalloproteinase (MMP)-8, an extracellular matrix-degrading collagenase that was significantly downregulated in Δ9-THC-treated SIV rhesus macaques [114]. Moreover, Δ9-THC-treated SIV rhesus macaques failed to upregulate pro-inflammatory miR-21, miR-141 and miR-222 and alpha/beta defensins, suggesting reduced intestinal inflammation [114]. Δ9-THC-treated SIV rhesus macaques also had increased expression of tight junction proteins (occludin, claudin-3), anti-inflammatory MUC13, keratin 8 (stress protection), prominin 1 (PROM1) (epithelial proliferation) and anti-HIV CCL5 [114]. There was significant collagen deposition in the paracortex and B-cell follicular lymph nodes from all vehicle-treated SIV-infected but not in the THC-treated, SIV-infected macaques, underscoring the ability of Δ9-THC to prevent lymph node fibrosis [114]. This finding is noteworthy, given that lymph node fibrosis is an irreversible consequence of HIV-induced chronic inflammation [114]. Furthermore, Δ9-THC suppressed gut T-cell proliferation and activation as demonstrated by Ki67, HLA-DR and PD-1 expression, and increased percentages of anti-inflammatory CD163+ macrophages [114]. Although Δ9-THC did not affect levels of CD4+ T cells, it significantly reduced levels of CD8+ T cells in peripheral blood at 14 and 150 days post-SIV infection [114]. Taken together, these findings support a role for selective miRNA and gene induction, and reduction in T-cell activation, in Δ9-THC-mediated suppression of intestinal inflammation in SIV [114].

The SIV/HIV reservoir is of importance because of its implications for HIV cure. Molina et al.[133] examined the effect of Δ9-THC treatment on the SIV reservoir within macaque spleens. Two long terminal repeat (LTR) DNA circles are markers of recent viral integration and provide a measure of viral DNA entry into the nucleus after integration of proviral DNA into host cell chromosomes. They demonstrated that episomal SIV 2-long terminal repeat (2-LTR) DNA circles were much lower in Δ9-THC-treated SIV-infected macaques compared with SIV-infected macaques not treated with Δ9-THC [133]. These findings suggest that Δ9-THC treatment may reduce SIV replication within tissue reservoirs, such as the spleen [133] -- a tissue very difficult to access in humans because of the risk of haemorrhage. In a study currently being led by Dr Nichole Klatt, her group is testing the hypothesis that cannabinoid administration to chronic SIV-infected nonhuman primates will decrease inflammation and the SIV reservoir [134]. Furthermore, they are determining cannabinoid levels and kinetics in the blood vs. gastrointestinal tract [134].

Human studies on cannabinoids and HIV infection: from observational studies to randomized controlled trials

Observational studies

Moving from simians to humans, variable results have been obtained from cross-sectional observational studies examining the association between CD4+ and CD8+ T-cell count and cannabis use [1,115–119]. In a longitudinal study involving PLWH and hepatitis C co-infection, cannabis use was not associated with reduction in CD4+ T-cell count [120]. No association has been found between cannabis and progression of HIV disease in the pre-ART era [122]. In the ART era, cannabis use has not been associated with 5-year mortality risk among over 3000 veterans followed between 2002 and 2010 [123]. Furthermore, cannabis smoking did not accelerate progression of liver disease in a cohort of PLWH and hepatitis C co-infection followed longitudinally [135].

In a cross-sectional observational study, which performed detailed immunological analyses, Manuzak et al.[124] examined the impact of cannabis use on peripheral immune cell frequency, activation and function in an observational study including 198 HIV-infected ART-treated PLWH. The overall frequency of CD4+ and CD8+ T cells among PBMCs was not altered in moderate or heavy cannabis-using individuals, compared with noncannabis-using individuals. However, the frequency of activated (HLA-DR+CD38+) T cells was significantly lower in the heavy cannabis-using group compared with the noncannabis-using individuals for both CD4+ and CD8+ T cells [124]. They also examined the frequency of intermediate monocytes (CD14+CD16+), which contribute to end-organ complications in PLWH because of their secretion of pro-inflammatory cytokines [136,137]. Intermediate monocyte frequency was significantly lower in the heavy cannabis-using group compared with noncannabis users. Finally, the frequency of nonclassical monocytes (CD14+CD16+), which also secrete pro-inflammatory cytokines and promote T-cell activation [136,137], was significantly reduced in the moderate and heavy cannabis-using group compared with the frequencies among noncannabis users [124]. Following in-vitro stimulation, frequencies of IL-10, IL-23, TNF-α-producing antigen-presenting cells were also much lower in heavy cannabis-using individuals vs. noncannabis using individuals [124]. High frequencies of CD16+ monocytes in circulation are of interest as they are elevated in individuals suffering from HIV-associated dementia [125,138]. Furthermore, in the central nervous system, specimens from patients with HIV-associated neurocognitive disorders obtained postmortem, high levels of CD16+ monocytes staining positive for HIV viral capsid protein p24 have been described [138]. In another observational study, Rizzo et al.[125] also examined frequencies of CD16+ monocytes between HIV-infected individuals using cannabis and HIV-infected donors not using cannabis. They observed lower numbers of CD16+CD163+ monocytes in HIV-infected persons using cannabis compared with donors when compared with HIV-infected persons not using cannabis donors [125]. In addition, plasma inducible protein 10 was also significantly lower in HIV-infected cannabis users than noncannabis users. Δ9-THC significantly decreased the percentage of monocytes expressing the CD16+, CD163+ and CD16+/CD163+ whereas CBD at the same concentration elicited no significant effects on the percentage of monocytes expressing CD16+, CD163+ and CD16+/CD163+[125]. These findings are relevant given that co-expression of CD16+ and CD163+ on monocytes is increased in postmortem brain tissue of persons with cognitive impairment [139].

In another cross-sectional study, Vidot et al.[126] examined markers of gut microbial translocation in addition to immune activation in ART-treated PLWH who use methamphetamines, which have been associated within greater monocyte activation and inflammation [100,140]. However, hazardous cannabis users (as determined by a score of eight or more on the Cannabis Use Disorder Identification Test-Revised (CUDIT-R) [141] had increased soluble CD14+ (sCD14+) compared with noncannabis users. Furthermore, there was no association between cannabis use severity with intestinal barrier integrity protein (iFABP), a marker of gastrointestinal enterocyte cell death [126]. Therefore, hazardous cannabis use in ART-treated methamphetamine users is unlikely to counteract the markers of gut mucosal damages [126]. However, because of inherent differences between populations, these results should not be generalized to individuals using cannabinoids for medicinal or recreational reasons in the absence of harzardous cannabis or methamphetamine use.

Given the importance of seminal fluid for HIV transmission, one group examined the association between cannabis use and seminal plasma viral load. In HIV-infected MSM on ART for at least 6 months, Ghosn et al.[127] measured HIV-RNA in seminal plasma and in blood plasma from two paired samples obtained 4 weeks apart. Out of 157 participants, 33 (21%) of individuals had STIs and residual blood plasma viral load. Multivariate adjustments were performed and PMBC-associated HIV-DNA and cannabis use during sexual intercourse were the only factors associated with significantly with seminal plasma viral load [OR 2.9 (1.2; 7.3)] [127]. However, because of the observational nature of this study, the high prevalence of STIs (which increase the seminal plasma viral load [142]) and the tendency of many individuals to use cannabis in combination with other substances, no causal relationship can be implied [127]. Indeed, cannabis use is more likely a by-proxy for factors contributing to increase seminal plasma viral load [127]. Furthermore, based on the evidence available to date, there is no biological basis to suggest that cannabis use induces inflammation in the genital tract, therefore more study is required before conclusions can be drawn.

In the aforementioned NIH-funded, ongoing study currently being led by Dr Nichole Klatt, her group will also test the hypothesis that cannabis use in the context of chronic HIV infection may decrease inflammation and the HIV reservoir in humans [134]. They will measure markers of inflammation, immunity, and the HIV reservoir from both blood and gastrointestinal tissues of PLWH reporting using cannabis daily compared with those reporting no drug use [134]. They will also assess ex vivo the mechanisms of cannabinoid anti-inflammatory activity through the use of cannabinoid receptor agonists in co-cultures [134].

Randomized-controlled trials in people living with HIV with primary endpoints outside of immunology

Moving onto randomized-controlled trials (RCTs) of cannabis in PLWH, two previous studies were performed to examine the effects of cannabinoids on peripheral neuropathy. Abrams et al.[143] randomly assigned 50 PLWH to smoke either cannabis (3.56% Δ9-THC) or identical placebo cigarettes, with the cannabinoids extracted three times daily for 5 days. Although cannabis was effective to reduce chronic HIV-associated neuropathic pain, effect on immunological parameters were not examined [143]. In another study examining neuropathic pain in PLWH, Coates et al. performed a placebo controlled double-blind randomized crossover trial of 1–8% Δ9-THC and placebo cigarettes administered four times daily for 5 days [144]. Although cannabis improved neuropathic pain vs. placebo, there were no significant effects on viral load or CD4+ T-cell counts reported [144]. The authors of a systematic review on the use of cannabis for reducing morbidity and mortality in HIV concluded that evidence for substantial effects on morbidity and mortality is currently limited and evidence for safety and efficacy of cannabis is lacking. Studies have been of short duration, in small numbers of patients and have focused on short-term measures of efficacy [145]. Furthermore, no study examined effect on inflammatory markers or HIV reservoir size.

Clinical trials in the context of HIV immunology and virology

With the goal of describing the short-term effects of cannabinoids on PLWH, 67 individuals who had been on ART for at least 8 weeks prior to the study were enrolled and randomized to either 3.95% of Δ9-THC cannabis cigarettes, 2.5 mg of dronabinol-containing capsule or placebo capsules three times daily prior to meals. In this study published in 2003, at baseline HIV-RNA level was under 50 copies/ml for 36 participants. Nearly half of participants were on either nelfinavir (55%) or indinavir (45%). This was notable because of concern for a potential drug interaction via hepatic cytochrome P-450 enzyme systems. However, neither smoked nor oral cannabinoids significantly changed HIV RNA levels, CD4+ and CD8+ T cells or protease inhibitor levels over a 21-day course of treatment [129]. Furthermore, other T-cell subpopulations, B cells, natural killer (NK) cells were not significantly altered. In addition, immune cell function appeared preserved based on assays for induced cytokine production, NK cell function and lymphocyte proliferation, as performed at baseline and weekly thereafter [130]. Bredt et al.[130] concluded that the few changes, which were statistically significant did not constitute any meaningful pattern of changes in immune phenotype or function.

In a phase 1 trial supported by the Canadian Institutes of Health Research (CIHR) Canadian HIV Trials Network (CTN-PT028), our group plans to examine the safety and tolerability of cannabinoid capsules with capsules of Δ9-THC:CBD in a 1 : 1 ratio or capsules of Δ9-THC:CBD in a 1 : 9 ratio when taken by PLWH with fully suppressed viral load for at least 3 years [146]. Questionnaires assessing quality of life and mood will be administered and effect on inflammatory markers and markers of peripheral blood HIV reservoir size will be assessed before and after study completion [146]. As this is a pilot study, a goal is to identify which steps in the protocol run smoothly vs. which steps require modification when designing a larger clinical trial powered to answer specific outcome questions related to human immunology and the HIV reservoir [146]. Studies examining the effects of cannabis in the context of HIV/SIV infection are summarized in Table 3.

Challenges of performing randomized-controlled trials with cannabinoid-based medicines

Due to confounding from observational studies, which limit assessment of cause and effect relationships, randomized, double-blinded, placebo-controlled clinical trials are the ideal method to study the effect of a drug on immune function. However, because of the psychological effects of Δ9-THC, it may be difficult if not impossible to blind participants and staff to treatment group allocation by having a placebo group. There are also concerns that giving participants agents, which could impede their cognitive function could be problematic for persons in certain types of jobs or while driving [147]. There is ongoing stigma related to cannabis and CBMs within and outside the medical community. Moreover, regulatory issues, with long time delays before receiving all the approvals necessary to execute a clinical trials, remain another impediment to conducting RCTs of CBMs.

The legalization of recreational cannabis in some US states and in Canada on 17 October 2018 (under The Cannabis Act) has brought along with it an increased interest by both the clinicians, researchers, public health authorities, government and the general public. Since the legalization of recreational cannabis by the Canadian Federal government, there has been a rise in funding opportunities available to better understand the health effects of cannabis, with millions of dollars in federal funding for cannabis research projects across the country being recently announced [148]. However, despite the legalization of recreational cannabis, performing clinical trials in Canada remains challenging because of lengthy regulatory hurdles.

Conclusion

Although the reasons for cannabis use have changed since the beginning of the HIV epidemic, for PLWH adherent to ART prevention and management of comorbidities is the paramount concern. Gut microbial translocation results in chronic systemic inflammation, driving these comorbidities. In-vitro studies show that CB2 activation of CD4+ T cells impairs productive HIV infection and CB2 agonists can reduce HIV reverse transcriptase activity. Simian studies have shown beneficial effects of Δ9-THC on reducing morbidity and mortality in SIV-infected macaques, and have demonstrated the ability of cannabinoids to restore gut--epithelial barrier integrity. In humans, the majority of cross-sectional studies neither demonstrate any harmful effect of cannabis or CBM on peripheral blood CD4+ or CD8+ T-cell count nor on HIV viral load. Cross-sectional studies in PLWH have also demonstrated favourable associations between cannabis use and a reduction in intermediate and nonclassical monocytes, which are harmful because of their ability to secrete pro-inflammatory cytokines and promote T-cell activation. Despite regulatory hurdles, further exploration of the potential benefits of cannabis and CBM on the immune system of PLWH in the context of randomized clinical trials will be helpful to elucidate the therapeutic potential of these agents in the management of chronic HIV. Ultimately, cannabis and CBM may play a role in slowing the development of HIV-associated morbidity and mortality, as an adjunct to ART, if their immunomodulatory properties can properly be exploited.

Acknowledgements

Funding: C.T.C. is supported by a Fonds de recherche du Québec-Santé (FRQ-S) clinician-researcher Junior 1 salary award. M.A.J. holds the CIHR Canada Research Chair tier 2 in Immuno-Virology. The CTN PT028 study is supported by the CIHR Canadian HIV Trials Network.

The authors have received free product from Tilray Inc. for use in a clinical trial (Canadian HIV Trials Network PT028), but no financial support was received for this article or other studies.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

AIDS; cannabis; HIV; inflammation; marijuana; medical cannabinoids

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