The two most important viral pathogens, based on mortality in the United States are HIV and influenza. The overall goal of this 5 year research plan is to test the hypothesis: ?9-tetrahydrocannbinol (?9-THC) attenuates antiviral responses against HIV and influenza virus through impairment of CD4+ T cell activation and function, and elicitation of antiviral specific CD8+ T cell effectors through CB1/CB2-dependent and -independent mechanisms. Our findings show that ?9-THC markedly impairs: (a) host resistance to influenza infection as evidenced by increased lung viral burden and decreased CD4+ and CD8+ T cell effectors;and (b) CD8+ T cell function, cytotoxic T lymphocyte activity and interferon 3 productions in vitro, in response to HIV gp120 and influenza-associated PB1. In addition, we show that cannabinoid treatment suppresses T cell function by impairing T cell activation via a mechanism involving rapid and sustained elevation in intracellular calcium [Ca+2]i, leading to T cell anergy. The rise in [Ca+2]i levels causes deregulation of the nuclear factor of activated T cells (NFAT) and impairs transcription of interleukin-2 and other NFAT-regulated cytokines. Additional results show that CB1-/-/CB2-/- mice are markedly more efficient in clearing influenza virus than wild type mice implicating a role for CB1 and/or CB2 in viral host resistance. Based on the above findings we will test our hypothesis using novel cell-based models with the following specific aims (SA): SA1 is to characterize impairment by ?9-THC, and the involvement of CB1/CB2, on the elicitation of antigen-specific multifunctional CD8+ T cells in response to HIV gp120 and influenza-associated PB1;SA2 is to characterize the impairment by ?9-THC, and the involvement of CB1/CB2, on CD4+ T cell activation and function induced by HIV gp120 and influenza-associated PB1;SA3 is in an in vivo surrogate model of HIV and influenza challenge, to characterize the impairment by ?9-THC, and involvement of CB1/CB2, on the elicitation of antigen-specific multifunctional CD8+ T cell responses to HIV gp120 and influenza-associated PB1;SA4 is in an in vivo surrogate model of HIV and influenza challenge, to characterize the impairment by ?9-THC, and involvement of CB1/CB2, on the CD4+ T cell response to HIV gp120 and influenza PB1;and SA5 is to determine the effect of 9-THC on the generation of multifunctional human peripheral blood (HPB) CD8+ T cells in response to HIV gp120 and influenza-associated M1. The significance of the proposed studies is that in their immunocompromised state, those infected with HIV or cancer patients are especially susceptible to infectious pathogens including influenza. Moreover, HIV and cancer patients are well known users of cannabis for stimulating appetite to alleviate the wasting syndrome that accompanies AIDS and as an antiemetic to relieve the nausea produced by cancer chemotherapy. In spite of the many HIV and cancer patients utilizing cannabis multiple times daily, an important data gap concerns the extent to which this practice may lead to a further diminution in immune competence and a more rapid progression of disease or mortality due to secondary infections.

Public Health Relevance

Patients suffering from AIDS and/or cancer are immune compromised and are also well-established users of cannabis, an illicit drug that is immunosuppressive;HIV patients to stimulate appetite and alleviate AIDS wasting syndrome and cancer patients to relieve nausea produced by cancer chemotherapy. This project assesses the consequences of cannabis on immunity against HIV and the common pathogen, influenza, which afflicts immune compromised individuals at a higher incidence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007908-19
Application #
8265686
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Avila, Albert
Project Start
2009-09-30
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
19
Fiscal Year
2012
Total Cost
$287,231
Indirect Cost
$95,171
Name
Michigan State University
Department
None
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Karmaus, Peer W F; Wagner, James G; Harkema, Jack R et al. (2013) Cannabidiol (CBD) enhances lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice. J Immunotoxicol 10:321-8
Ngaotepprutaram, Thitirat; Kaplan, Barbara L F; Carney, Stephen et al. (2013) Suppression by ýý(9)-tetrahydrocannabinol of the primary immunoglobulin M response by human peripheral blood B cells is associated with impaired STAT3 activation. Toxicology 310:84-91
Karmaus, Peer W F; Chen, Weimin; Crawford, Robert et al. (2013) ýý9-tetrahydrocannabinol impairs the inflammatory response to influenza infection: role of antigen-presenting cells and the cannabinoid receptors 1 and 2. Toxicol Sci 131:419-33
Ngaotepprutaram, Thitirat; Kaplan, Barbara L F; Kaminski, Norbert E (2013) Impaired NFAT and NF?B activation are involved in suppression of CD40 ligand expression by ?(9)-tetrahydrocannabinol in human CD4(+) T cells. Toxicol Appl Pharmacol 273:209-18
Pires, Paulo W; Girgla, Saavia S; McClain, Jonathon L et al. (2013) Improvement in middle cerebral artery structure and endothelial function in stroke-prone spontaneously hypertensive rats after macrophage depletion. Microcirculation 20:650-61
Karmaus, Peer W F; Chen, Weimin; Crawford, Robert B et al. (2011) Deletion of cannabinoid receptors 1 and 2 exacerbates APC function to increase inflammation and cellular immunity during influenza infection. J Leukoc Biol 90:983-95
Kaplan, Barbara L F; Lawver, Jody E; Karmaus, Peer W F et al. (2010) The effects of targeted deletion of cannabinoid receptors CB1 and CB2 on intranasal sensitization and challenge with adjuvant-free ovalbumin. Toxicol Pathol 38:382-92
Lu, Haitian; Kaplan, Barbara L F; Ngaotepprutaram, Thitirat et al. (2009) Suppression of T cell costimulator ICOS by Delta9-tetrahydrocannabinol. J Leukoc Biol 85:322-9
Kaplan, Barbara L F; Springs, Alison E B; Kaminski, Norbert E (2008) The profile of immune modulation by cannabidiol (CBD) involves deregulation of nuclear factor of activated T cells (NFAT). Biochem Pharmacol 76:726-37
Buchweitz, John P; Karmaus, Peer W F; Williams, Kurt J et al. (2008) Targeted deletion of cannabinoid receptors CB1 and CB2 produced enhanced inflammatory responses to influenza A/PR/8/34 in the absence and presence of Delta9-tetrahydrocannabinol. J Leukoc Biol 83:785-96

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