9-THC is the major psychoactive cannabinoid in marijuana. Advanced understanding of its pharmacology and the major cannabinoid receptor subtypes (CB1 and CB2) as well as their localization (CB2predominantly on B lymphocytes and natural killer cells) has resulted in identification of multisystemic biomedical effects. Particularly important is the potential of 9-THC modulation of immune function in human immunodeficiency virus (HIV) infected individuals. Our studies indicate that chronic 9-THC treatment attenuates viral load and tissue inflammation in simian immunodeficiency virus (SIV) infected non-human primates, significantly decreasing morbidity and mortality from SIV infection. In addition, 9-THC decreased viral replication in an in vitro assay. While the ability of cannabinoids to suppress inflammation and viral replication has been reported by others and confirmed by our ongoing studies, the mechanisms involved are not known. Preliminary data obtained in preparation for this application revealed increased expression of a distinct miRNA profile associated with decreased immune activation and anti-inflammatory properties (based on predicted targets) in CD4+ T lymphocytes, intestinal mucosa, and brain of THC-treated SIV-infected animals. These findings clearly suggest that the overall mechanisms mediating the protective effects of cannabinoids involve novel epigenomic regulatory factors/mechanisms in need of systematic investigation. The overall hypothesis of this proposal is that chronic 9-THC treatment decreases pro-inflammatory gene expression and viral replication through epigenomic (non-coding RNAs and DNA methylation) mechanisms. As a result, chronic cannabinoid treatment delays disease progression in SIV-infected non-human primates. This hypothesis will be tested with the following specific aims: 1. Demonstrate that chronic cannabinoid treatment decreases tissue inflammation in SIV-infected rhesus macaques. 2. Identify the epigenomic (including miRNAs and DNA methylation) mechanisms of cannabinoid-induced suppression of inflammation in SIV-infected rhesus macaques. 3. Examine the direct and indirect epigenomic mechanisms by which cannabinoids decrease viral replication. The proposed studies will explore the epigenomic (miRNA and DNA methylation) mechanisms involved in the anti-inflammatory effects and suppression of viral replication associated with prolonged survival in chronic THC-treated SIV-infected animals.
Project Narrative The proposed studies will explore the epigenomic (miRNA and DNA methylation) mechanisms involved in the anti-inflammatory effects and suppression of viral replication associated with prolonged survival in chronic THC-treated SIV-infected animals. The expected results will have a profound impact on the potential development of targeted therapeutic interventions to ameliorate HIV disease progression.
|Simon, Liz; Song, Keijing; Vande Stouwe, Curtis et al. (2016) Î”9-Tetrahydrocannabinol (Î”9-THC) Promotes Neuroimmune-Modulatory MicroRNA Profile in Striatum of Simian Immunodeficiency Virus (SIV)-Infected Macaques. J Neuroimmune Pharmacol 11:192-213|
|Chandra, Lawrance C; Kumar, Vinay; Torben, Workineh et al. (2015) Chronic administration of Î”9-tetrahydrocannabinol induces intestinal anti-inflammatory microRNA expression during acute simian immunodeficiency virus infection of rhesus macaques. J Virol 89:1168-81|
|Nichols, Whitney A; Birke, Leslie; Dufour, Jason et al. (2015) Characterization of the Genital Microenvironment of Female Rhesus Macaques Prior to and After SIV Infection. Am J Reprod Immunol 74:508-22|
|Molina, Patricia E; Amedee, Angela M; Winsauer, Peter et al. (2015) Behavioral, Metabolic, and Immune Consequences of Chronic Alcohol or Cannabinoids on HIV/AIDs: Studies in the Non-Human Primate SIV Model. J Neuroimmune Pharmacol 10:217-32|
|Molina, Patricia E; Amedee, Angela M; LeCapitaine, Nicole J et al. (2014) Modulation of gut-specific mechanisms by chronic Î´(9)-tetrahydrocannabinol administration in male rhesus macaques infected with simian immunodeficiency virus: a systems biology analysis. AIDS Res Hum Retroviruses 30:567-78|
|Amedee, Angela M; Nichols, Whitney A; LeCapitaine, Nicole J et al. (2014) Chronic Î”â¹-tetrahydrocannabinol administration may not attenuate simian immunodeficiency virus disease progression in female rhesus macaques. AIDS Res Hum Retroviruses 30:1216-25|
|Molina, Patricia E; Amedee, Angela; LeCapitaine, Nicole J et al. (2011) Cannabinoid neuroimmune modulation of SIV disease. J Neuroimmune Pharmacol 6:516-27|