Pulmonary and Immunologic Effects of Marijuana Use on HIV and Viral Immunity
Principal Investigator: M D Roth
Abstract: For the past 25 years this grant has investigated health-related consequences associated with marijuana (MJ) smoking and exposure to delta9-tetrahydrocannabinol (THC). We have carried this out with a unique combination of human studies, in vitro experiments, and animal models. In this competing renewal we focus on the role of cannabinoids as immunoregulatory molecules and the mechanisms by which THC suppresses host immunity and increases susceptibility to HIV infection. We have demonstrated that peripheral blood mononuclear cells (PBMC) express cannabinoid receptors and that receptor expression is modulated in MJ smokers, consistent with a direct effect of inhaled THC on circulating immune cells. In modeling the effects of THC on PBMC in vitro, we discovered that THC suppresses human T cell activation and skews cytokine production toward an immunosuppressive profile. Our preliminary studies suggest that both the initiation and maintenance of antigen-specific immunity is impaired by THC. Even more striking, when human PBMC were engrafted into SCID mice, exposure to THC suppressed their capacity to produce IFN-y, enhanced their susceptibility to HIV infection, and dramatically increased systemic viral load. We hypothesize that similar immune modulation occurs in habitual MJ users and may impact their ability to respond to viral infections and vaccines. Three specific aims are proposed: 1) to define the mechanisms by which THC promotes HIV infection in vivo in the huPBL-NOD/SCID/IL2r-gamma-null model, 2) to investigate the mechanisms by which THC alters the induction and maintenance of antigen-specific immune responses against HIV and Hepatitis B antigens in vitro and in the huPBL-NOD/SCID/IL2r-gamma-null model, and 3) to examine the impact of habitual MJ smoking on humoral and cellular immunity to Hepatitis B (HBV) vaccination under controlled MJ exposure conditions. By the conclusion of this work we will have defined several mechanisms by which THC interacts with and promotes HIV infection. We will also have gained important insight into the impact of THC on the generation of anti-viral immunity and the mechanisms mediating these effects. Our prospective vaccination study will be the first of its kind to directly examine MJ smoking for its impact on a clinically relevant immune response. These findings will help define the interrelationships between MJ abuse and opportunistic infections and provide insight into the appropriate design/use of future HIV and HBV vaccine strategies.
Funding Period: ----------------1982 - ---------------2011-
more information: NIH RePORT
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Clinical Pharmacology and Therapeutics Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224 6823, USA
Am J Addict 15:8-14. 2006....
- Quitting among non-treatment-seeking marijuana users: reasons and changes in other substance useMarc L Copersino
Clinical Pharmacology and Therapeutics Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland, USA
Am J Addict 15:297-302. 2006..These findings suggest areas for further research on spontaneous recovery from marijuana use...
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Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at UCLA, 37 131 CHS, Los Angeles, CA 90095, USA
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Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA
Am J Drug Alcohol Abuse 36:311-9. 2010..Cannabis withdrawal can be a negative reinforcer for relapse, but little is known about its association with demographic characteristics...
- Differential expression of intracellular and extracellular CB(2) cannabinoid receptor protein by human peripheral blood leukocytesJulie T Castaneda
Division of Pulmonary and Critical Care Medicine, Department of Medicine, CHS 37 131, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1690, USA
J Neuroimmune Pharmacol 8:323-32. 2013..The differential role of intracellular and extracellular CB(2) receptors in mediating ligand signaling and immune function remains to be determined...
- Reconstitution of huPBL-NSG mice with donor-matched dendritic cells enables antigen-specific T-cell activationAiri Harui
Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1690, USA
J Neuroimmune Pharmacol 6:148-57. 2011....