This phenomenon may explain why isolated compounds derived from cannabis appear only capable of exerting a limited effect as seen in drugs such as with the synthetic ∆-9 THC drug, dronabinol. To what extent each of these components confers anti-inflammatory benefits is a current focus of research. To what extent each of these components confers anti-inflammatory benefits is a current focus of research.An extensive literature beyond the scope of this review demonstrates persistently elevated levels of inflammatory and immune activation biomarkers even in PWH on antiretroviral therapy who have achieved plasma HIV RNA levels less than 50 copies/mL, designated “virally suppressed”. These include interleukin-6 , C-reactive protein and tumor necrosis factor alpha, CD4+ T cell depletion in gut lymphoid tissue persist, activated T cells are increased, and many immune cells are senescent. PWH also have a dysfunctional gut epithelial barrier , an increase in the permeability of the intestinal barrier accompanied by gut dysbiosis and immune dysregulation from loss of T cells in the GALT, resulting in activation of pro-inflammatory soluble CD14 , a response to circulating bacterial products, or microbial translocation . The central nervous system is an important site of inflammation in HIV, as demonstrated by measuring inflammatory biomarkers in cerebrospinal fluid, by brain magnetic resonance spectroscopy, and by positron emission tomography using microglial activation markers. Several mechanisms contribute to the persistence of inflammation in virally suppressed PWH. These include coinfections and gut dysbiosis. Cytomegalovirus co-infection is highly prevalent in PWH; CMV replication is frequently reactivated, triggering an inflammatory response. As mentioned above, gut microbial dysbiosis, which promotes dysfunction of the gut epithelial barrier, drying room resulting in a positive feedback loop sustained by increased microbial translocation of pro-inflammatory antigens such as lipopolysaccharide and subsequent immune activation and chronic inflammation.

Whereas normal commensal flora contribute to tolerance and balance between T helper subsets, loss or replacement of these beneficial flora leads to loss of T-helper type 1 function, amplifying GALT dysfunction in HIV infection. Depletion of Th17 cells in the GALT leads to reduced IL-22 production, diminishing epithelium repair processes and maintenance of tight gap junctions. Such barrier defects create a pathway for microbial products to escape the gut lumen and enter the systemic circulation. The entry of microbial products into the blood, known as microbial antigen translocation triggers the innate immune response and release of pro-inflammatory cytokines, such as interleukin -1β, TNF-α and others. Abundant data show activation of the NLRP3 inflammasome in virally suppressed PWH. Hepatitis C virus co-infection is common in PWH and may be another source of microbial translocation that drives inflammation. Plasma levels indicative of microbial translocation in HIV-HCV co-infection were higher than in monoinfected PWH virally suppressed on ART. PWH co-infected with HCV had a marked increase in markers of microbial translocation than uninfected healthy controls, whereas the plasma 16S rDNA was relatively similar, suggesting that it is the immune activation that persists as opposed to the circulating bacterial products. Tudesq and colleagues demonstrated for the first time that the plasma 16S rDNA levels increased with the duration of HIV infection in HIV-HCV co-infection, independent of HCV progression.Increased inflammation in virally suppressed PWH as described above is associated with adverse health outcomes such as myocardial infarction and even death. Persistent inflammation also affects the central nervous system , where microglia and astrocytes are chronically activated , ddimer, IL-6, CRP, monocyte chemoattractant protein 1 , soluble CD14 and sCD40L. Adjusting for age, comorbidity status, sex, ethnicity, AIDS status, current and nadir CD4, and virologic suppression on ART, factor analyses reduced the dimensionality of the biomarkers, yielding three factors, one of which was loaded on d-dimer, IL-6 and CRP and was correlated with worse depressed mood. We also reported that poorer social support was associated with higher levels of plasma MCP-1, IL-8 and VEGF, as well as CSF MCP-1 and IL-6 , suggesting that that enhancing social support might be an intervention to reduce inflammation and its associated adverse outcomes among PWH.The ECS comprises a network of receptors, endogenous ligands and enzymes expressed in diverse cell types.

Among the many functions of the ECS is regulation of energy use and substrate metabolism to maintain homeostasis. Components of exogenously administered cannabis bind to EC receptors, thereby modulating the function of the ECS. ECS signaling pathways have been pursued as a target for future pharmacotherapy to reduce inflammation and provide therapy in pathological conditions. The cannabinoid receptors type-1 and -2 are expressed in most tissues. CB2Rs are densely expressed in immune tissue and organs in diverse cell types including macrophages, splenocytes, microglia, monocytes, and T-cells resident in the thymus, spleen, and bone marrow and tonsils, providing a mechanism by which cannabinoids can exert anti-inflammatory effects. CB1Rs are most abundant in the brain, where they serve to modulate neurotransmitter activities, thereby mediating effects of phytocannabinoids on neurobehavior. They are particularly highly expressed in nociceptive areas of the CNS, as well as in the cerebellum, hippocampus, limbic system, and basal ganglia. They are not found in the medullary respiratory centers and thus, unlike opioids, do not cause respiratory depression. CB1Rs are also expressed on immune, cardiac, and testicular cells. In the GI tract, CB1Rs are involved in feeding, gastrointestinal motility, satiety signaling and energy balance. CB1R peripheral activity includes lipogenesis and inhibition of adiponectin, found at elevated levels in obese and diabetic individuals . CB1R signaling has been linked to increased levels of free fatty acids, low HDL, high triglycerides and insulin resistance. The two main endocannabinoids are arachidonoyl ethanolamide, or anadamide , and 2-arachidonoylglycerol , both derived from lipid precursors and synthesized on demand. Endocannabinoids in the postsynaptic neuron are released into the synaptic cleft, and travel retrograde to the presynaptic neuron, where they inhibit neurotransmitter release. The principal enzymes for degradation of ECs are fatty acid amide hydrolase and monoacylglycerol lipase . Additional EC-degrading enzymes include cyclooxygenase-2 , lipoxygenase , serine esterases and cytochrome P450.The anti-inflammatory effects of exogenous cannabinoids are mediated by the ECS , likely through CB2Rs in the periphery that have immunomodulatory functions.

Both preclinical and clinical evidence support theseanti-inflammatory effects of exogenous cannabinoids, particularly THC and CBD. This may be particularly important in the context of HIV, which is characterized by persistent inflammation as described above. For example, PWH heavy cannabis users had decreased frequencies of T-cells bearing the activation marker HLA-DR+ CD38+ CD4+ compared to non-cannabis-using individuals. Heavy cannabis users also showed reduced frequencies of antigen-presenting cells that produced pro-inflammatory interleukin-23 and tumor necrosis factor-α. In another study, HIV-infected cannabis users had lower IFN-γ-inducible protein 10 levels in plasma. In an experimental study examining the interaction between the ECS and cytokine networks in humans, CB1 and CB2 expression were significantly induced by TNF-α, IL-β, and IL-6. CBD may be a particularly potent anti-inflammatory component of cannabis. CBD reduces pro-inflammatory cytokines, inhibits T cell proliferation and reduces migration and adhesion of immune cells. These effects translate to improved outcomes in disease models. Thus, CBD protected against the deleterious effects of inflammation in a viral model of multiple sclerosis. Cannabidivarin , structurally similar to CBD, is a non-psychoactive cannabinoid found in cannabis. Very little work has been conducted on CBDV in PWH. In one study, CBDV was safe but failed to reduce neuropathic pain in patients with HIV. In the laboratory, it has been shown that CBDV decreases fat formation and inflammation in human skin cells. Many anti-inflammatory actions of cannabinoids may be mediated through the gut, particularly through stabilization of the gut barrier. The gut barrier is composed of epithelial cells, tight junctions, and a mucus layer. It controls beneficial nutrient absorption and protects against the deleterious invasion of pathogenic bacteria and toxins from the gut lumen into the blood. The ECS, how to trim cannabis together with the gut microbiota, regulates epithelial barrier permeability. In an animal model of HIV, macaques infected with simian immunodeficiency virus showed increased markers of inflammation and immune activation in epithelial crypt cells; these markers were reduced after chronic THC administration. Exposure to phytocannabinoids may reduce neural injury by decreasing excitotoxicity and neuroinflammation. In a large cohort of PWH, we recently reported that neurocognitive impairment was less frequent in cannabis users than non-users, regardless of viral suppression. In comparison, cannabis exposure was not related to NCI among PWoH. Unlike many prior reports, this analysis carefully controlled for any non-cannabis substance use disorders, positive urine toxicology for other illicit drugs and any past methamphetamine use disorder, positive breathalyzer test for alcohol, major depressive disorder and HIV disease characteristics. A possible mechanism of the specificity of the benefits of cannabis only for PWH is the anti-inflammatory effect of cannabis, which may be particularly important for PWH who have persistent inflammation despite good antiretroviral treatment. In contrast to cannabis’s beneficial actions in PWH, research on PWoH typically reports adverse effects on brain development and neurocognition. Examples include attentional and memory deficits, behavioral problems and structural and functional brain changes. The data are particularly concerning for adolescents. It is possible that PWH are less likely to suffer these adverse consequences than PWoH because of the counterbalancing effects of cannabis in reducing neuroinflammation, as we discussed when considering stroke. In an animal study, euroinflammation, measured as levels of TNFα, IL-1β, IL-6 and MCP-1, was reduced in the striatum of SIV-infected animals treated with THC.

Enteroendocrine signaling and the vagus nerve may provide a mechanism through which the gut microbiota may influence the central nervous system. Additionally, signaling through CB1Rs is influenced by Akkermansia muciniphila and administration of this organism to obese and type 2 diabetic mice increased intestinal levels of ECs that control gut inflammation and the gut barrier. These relationships between the gutmicrobiota and the ECS may be therapeutically useful. Thus, in zebrafish treated with a probiotic formulation for 30 days, gene expression of FAAH and MAGL, the enzymes responsible for degradation of the endocannabinoids AEA and 2-AG, decreased. Thus, probiotic treatment enhanced endocannabinoid signaling and improved gut integrity. Gut bacteria control the differentiation and function of immune cells in the intestine, periphery, and brain. There is increasing evidence that gut microbiota and the immune system are critical factors in the pathogenesis of neurodevelopmental, psychiatric and neurodegenerative disease as microbiota immunomodulation orchestrates communication between the gut and brain. Some cognitive domains are subject to immune-mediated CNS injury from HIV-induced microglial activation and contribute to HIV-related cognitive dysfunction. Furthermore, microglia are exquisitely responsive to the gut microbiome and commensal bacteria support the maintenance of microglia in normal homeostasis conditions. When microbiota is absent, microglia lose the ability to mature, becoming defected in differentiation, and function. In a study with germ-free mice, severely defected microglia led to impaired innate immune responses. LPS activates microglial cells leading to neuroinflammation and when chronic, is a likely contributor to CNS pathologies, via a leaky gut–brain barrier. Microbial antigen translocation refers to the entry of bacterial, fungal and viral components, such as LPS, and metabolites, such as short-chain fatty acids , cross from the gut lumen into the bloodstream. The endogenous cannabinoid, AEA, contributes to the process by which the gut immune system actively tolerates such microbial antigens. In HIV, MAT is associated with monocyte activation and inflammation. Thus, β-D-glucan is a microbially derived antigen that serves as one index of MAT. The anti-inflammatory effects of cannabinoids may be beneficial with respect to HIV reservoirs, which are the principal barrier to HIV cure. We analyzed HIV DNA in blood as a marker of reservoir size in men who had sex with men and initiated ART within a median of 4 months of estimated date of HIV infection. All achieved suppressed HIV RNA within a median of 5 months. Exclusive use of cannabis, as compared to no substance use or use of other drugs, was associated with a faster decay of HIV DNA during suppressive ART. These results are in line with prior reports of reduced HIV replication and cellular infection rate in the presence of cannabinoids in vitro. Thus, the potential anti-inflammatory effects of cannabis could translate to a beneficial impact in reducing HIV persistence. However, there is no consistent evidence that cannabis use affects levels of plasma HIV RNA. In addition to their expression in the peripheral immune system, CB2Rs are also expressed in the CNS . In humans, the bulk of CB2R expression is by microglia and astrocytes, consistent with a role in neuroinflammation.