Cannabinoid Administration Attenuates the Progression of Simian Immunodeficiency Virus

Abstract

D9 -Tetrahydrocannabinol (D 9 -THC), the primary psychoactive component in marijuana, is FDA approved to ameliorate AIDS-associated wasting. Because cannabinoid receptors are expressed on cells of the immune system, chronic D 9 -THC use may impact HIV disease progression. We examined the impact of chronic D 9-THC administration (0.32 mg/kg im, 2Âdaily), starting 28 days prior to inoculation with simian immunodeficiency virus (SIV mac251 ; 100 TCID 50 /ml, iv), on immune and metabolic indicators of disease during the initial 6 month asymptomatic phase of infection in rhesus macaques. SIV mac251 inoculation resulted in measurable viral load, decreased lymphocyte CD4 þ /CD8 þ ratio, and increased CD8 þ proliferation. D 9 -THC treatment of SIV-infected animals produced minor to no effects in these parameters. However, chronic D 9 -THC administration decreased early mortality from SIV infection ( p ¼ 0.039), and this was associated with attenuation of plasma and CSF viral load and retention of body mass ( p ¼ NS). In vitro, D 9 -THC (10 mm) decreased SIV (10 TCID 50 ) viral replication in MT4-R5 cells. These results indicate that chronic D 9 -THC does not increase viral load or aggravate morbidity and may actually ameliorate SIV disease progression. We speculate that reduced levels of SIV, retention of body mass, and attenuation of inflammation are likely mechanisms for D 9 -THC-mediated modulation of disease progression that warrant further study.T he cannabinoids including cannabidiol, cannabinol, and D 9 -tetrahydrocannabinol (D 9 -THC) exert their effects by binding to two major subtypes of cannabinoid receptor, CB1 and CB2.1 The CB1 receptor is preferentially expressed in the brain where it mediates neurobehavioral effects. The CB2 receptor is expressed primarily in peripheral tissues, particularly in immune cells where they have been shown to affect cytokine production, lymphocyte phenotype, function and survival, cell-mediated immunity, and balance of Th1/ Th2 cells.2 With the advent of highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV) infection has become a chronic disease frequently coexisting with chronic use of drugs of abuse, including marijuana. Using a well-established nonhuman primate model of HIV disease, we examined the impact of chronic intramuscular D 9 -THC (provided by the National Institute on Drug Abuse, Research Technical Branch, Rockville, MD) administration on the early phase of simian immunodeficiency virus (SIV) infection in age-matched (4-6 years old) and body weight-matched healthy male Indian-derived rhesus macaques. Chronic administration of D 9 -THC [or 0.05 ml/kg vehicle (VEH)] was initiated prior to SIV with 0.18 mg/kg, a dose that eliminated responding in a complex operant behavioral task in almost all of the subjects. The dose was subsequently increased for each subject to 0.32 mg/kg, over

Chronic Administration of Δ 9 -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

“…Chronic THC administration to SIV-infected macaques reduced plasma viral loads, protected against infection-induced GI inflammation, and prolonged survival (9). More recently, we also demonstrated that chronic THC administration to SIV-infected macaques modulated duodenal T cell populations, stimulated a proTh2 cytokine profile, and more importantly, decreased crypt cell ϩ (A to C, D, and E) staining cells are shown in red (permanent red substrate).…”

“…While the effects of the cannabinoids on inflammation and viral replication have been reported by others and confirmed by our recent macaque studies (9,23), mechanistic studies to elucidate these protective effects are needed. Several recent reports have linked altered microRNA (miRNA) expression, a newly identified class of noncoding RNAs that function to regulate gene expression to alcohol, morphine, and cocaine addiction (25)(26)(27)(28)(29).…”

Immunoregulatory Role of Cannabinoids during Infectious Disease

“…Treatment with the cannabinoid decreased early mortality, however [72,74]. Interestingly, this effect is gender-dependent, as female macaques in the same condition showed that THC treatment did not protect them from early mortality [75].…”

Immunomodulatory Properties of Kappa Opioids and Synthetic Cannabinoids in HIV-1 Neuropathogenesis

“…Chronic THC administration decreased early mortality from simian immunodeficiency virus (SIV) infection, and this was associated with attenuation of plasma and CSF viral load and retention of body mass (Molina et al 2010). In vitro, THC decreased SIV viral replication in MT4-R5 cells (Molina et al 2010).…”

“…The work thus far on the neuroprotective role of synthetic cannabinoids has focused on mechanisms related to the CB1 and CB2 receptors, non-CB1/CB2-receptor mediated mechanisms must be considered as well, especially since candidate CB receptors are emerging (Cabral and Griffin-Thomas 2009). While short-term clinical studies have not demonstrated a deleterious effect of cannabinoids on HIV disease (Bredt et al 2002;Kosel et al 2002;Abrams et al 2003), and much of the evidence supporting the neuroprotective effects of synthetic cannabinoids is also based on in vitro studies, encouraging evidence has emerged from studies using and SIV monkey models and hu-PBL/HIVE mouse models (Gorantla et al 2010;Molina et al 2010). Additional in vivo investigations would serve to flesh out the potential role of synthetic compounds in a treatment modality targeting HIV neuropathogenesis.…”