title: Modulation of gut-specific mechanisms by chronic δ(9)-tetrahydrocannabinol administration in male rhesus macaques infected with simian immunodeficiency virus: a systems biology analysis.
abstract: Our studies have demonstrated that chronic Δ(9)-tetrahydrocannabinol (THC) administration results in a generalized attenuation of viral load and tissue inflammation in simian immunodeficiency virus (SIV)-infected male rhesus macaques. Gut-associated lymphoid tissue is an important site for HIV replication and inflammation that can impact disease progression. We used a systems approach to examine the duodenal immune environment in 4- to 6-year-old male rhesus monkeys inoculated intravenously with SIVMAC251 after 17 months of chronic THC administration (0.18-0.32 mg/kg, intramuscularly, twice daily). Duodenal tissue samples excised from chronic THC- (N=4) and vehicle (VEH)-treated (N=4) subjects at ∼5 months postinoculation showed lower viral load, increased duodenal integrin beta 7(+)(β7) CD4(+) and CD8(+) central memory T cells, and a significant preferential increase in Th2 cytokine expression. Gene array analysis identified six genes that were differentially expressed in intestinal samples of the THC/SIV animals when compared to those differentially expressed between VEH/SIV and uninfected controls. These genes were identified as having significant participation in (1) apoptosis, (2) cell survival, proliferation, and morphogenesis, and (3) energy and substrate metabolic processes. Additional analysis comparing the duodenal gene expression in THC/SIV vs. VEH/SIV animals identified 93 differentially expressed genes that participate in processes involved in muscle contraction, protein folding, cytoskeleton remodeling, cell adhesion, and cell signaling. Immunohistochemical staining showed attenuated apoptosis in epithelial crypt cells of THC/SIV subjects. Our results indicate that chronic THC administration modulated duodenal T cell populations, favored a pro-Th2 cytokine balance, and decreased intestinal apoptosis. These findings reveal novel mechanisms that may potentially contribute to cannabinoid-mediated disease modulation.
authors.affiliation: Departments of Physiology, Pharmacology, and Medicine, and Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center , New Orleans, Louisiana.
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Molina
authors.forename: Angela M
authors.initials: AM
authors.lastname: Amedee
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: LeCapitaine
authors.forename: Jovanny
authors.initials: J
authors.lastname: Zabaleta
authors.forename: Mahesh
authors.initials: M
authors.lastname: Mohan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Winsauer
authors.forename: Curtis
authors.initials: C
authors.lastname: Vande Stouwe
authors.forename: Robin R
authors.initials: RR
authors.lastname: McGoey
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Auten
authors.forename: Lynn
authors.initials: L
authors.lastname: LaMotte
authors.forename: Lawrance C
authors.initials: LC
authors.lastname: Chandra
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Birke
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D013759:Dronabinol / Q000008:administration & dosage*; D004386:Duodenum / Q000473:pathology* / Q000821:virology*; D020869:Gene Expression Profiling; D007155:Immunologic Factors / Q000008:administration & dosage*; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D046228:Microarray Analysis; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000473:pathology* / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000302:isolation & purification*; D049490:Systems Biology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D019562:Viral Load
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D013759:Dronabinol