Effects of marijuana on peripheral and central nervous immune markers in marijuana smokers and HIV-infected subjects

Abstract

Marijuana can lower cellular immune responses and inhibit inflammation. The goal of this dissertation was to examine the effects of marijuana on peripheral and central nervous system (CNS) immune markers in current marijuana users (MJ) and HIV-infected marijuana users (HIV+MJ). We hypothesized that marijuana would lower cell activation and reduce inflammatory cytokine secretion in the CNS. An in vitro monocyte activation model using lipopolysaccharide was developed to assess baseline and activation immune markers in healthy individuals using flow cytometry and the kinetics of HIV infection between activated and non-activated monocytes was studied. Peripheral blood mononuclear cells were isolated from HIV+MJ, HIV+ subjects (HIV+), MJ and sero-negative controls (SN). Cells were stained for cannabinoid receptors (CB) and immune markers and were analyzed using flow cytometry. Cytokines from age-matched subjects who provided cerebral spinal fluid (CSF) were measured by Luminex. After lipopolysaccharide stimulation, monocytes increased CD16 and CD69 surface expression (p<0.05). The activated monocyte phenotype was supported by an increase in TNF-α production (p<0.05). The activated monocytes also had increased CCR5 expression (p=0.05) and bound more R5-tropic HIV than non-activated monocytes (p<0.05). CB1 and CB2 receptors were found on monocytes and significant group differences were observed in the expression of inflammatory CD16 (p<0.0001) and CCR5 (p<0.003) on monocytes. CD14+CD16+ monocytes were higher in HIV+MJ than in HIV+ subjects (p=0.0054), and in MJ users than in SN subjects (p<0.0001). CCR5 expression was significantly higher in MJ users than SN subjects (p<0.0001); however, no difference in CCR5 expression was found between HIV+MJ users and HIV subjects (p=0.4). The duration of marijuana use correlated with the levels of CD14+CD16+ (r=0.53, p<0.001) and CD14+CCR5+ expression (r=0.24, p=0.049). Inflammatory cytokines (fractalkine, INF-α2 and IL-1α) and chemoattractants (MCP-1, IP-10 and IL-8) were all significantly higher in the HIV+MJ and MJ than in respective controls. The higher levels of inflammatory cytokines and activated monocytes in HIV+MJ and MJ groups, as well as their correlation with lifetime MJ use, suggest marijuana induced inflammation in the periphery and CNS. Moreover, higher CCR5 expression on the activated monocytes in MJ suggests that marijuana use may render susceptibility to HIV infection.