title: Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues.
abstract: The role of the adenosine (ADO) pathway in human immunodeficiency virus type 1/simian immunodeficiency virus (HIV-1/SIV) infection remains unclear. We compared SIVsab-induced changes of markers related to ADO production (CD39 and CD73) and breakdown (CD26 and adenosine deaminase) on T cells from blood, lymph nodes, and intestine collected from pigtailed macaques (PTMs) and African green monkeys (AGMs) that experience different SIVsab infection outcomes. We also measured ADO and inosine (INO) levels in tissues by mass spectrometry. Finally, we assessed the suppressive effect of ADO on proinflammatory cytokine production after T cell receptor stimulation. The baseline level of both CD39 and CD73 coexpression on regulatory T cells and ADO levels were higher in AGMs than in PTMs. Conversely, high INO levels associated with dramatic increases in CD26 expression and adenosine deaminase activity were observed in PTMs during chronic SIV infection. Immune activation and inflammation markers in the gut and periphery inversely correlated with ADO and directly correlated with INO. Ex vivo administration of ADO significantly suppressed proinflammatory cytokine production by T cells in both species. In conclusion, the opposite dynamics of ADO pathway-related markers and contrasting ADO/INO levels in species with divergent proinflammatory responses to SIV infection support a key role of ADO in controlling immune activation/inflammation in nonprogressive SIV infections. Changes in ADO levels predominately occurred in the gut, suggesting that the ADO pathway may be involved in sparing natural hosts of SIVs from developing SIV-related gut dysfunction. Focusing studies of the ADO pathway on mucosal sites of viral replication is warranted.
  
  
  OBJECTIVE
  The mechanisms responsible for the severe gut dysfunction characteristic of progressive HIV and SIV infection in humans and macaques are not completely elucidated. We report that ADO may play a key role in controlling immune activation/inflammation in nonprogressive SIV infections by limiting SIV-related gut inflammation. Conversely, in progressive SIV infection, significant degradation of ADO occurs, possibly due to an early increase of ADO deaminase complexing protein 2 (CD26) and adenosine deaminase. Our study supports therapeutic interventions to offset alterations of this pathway during progressive HIV/SIV infections. These potential approaches to control chronic immune activation and inflammation during pathogenic SIV infection may prevent HIV disease progression.
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Tianyu
authors.initials: T
authors.lastname: He
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Egidio
authors.initials: E
authors.lastname: Brocca-Cofano
authors.affiliation: Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Delbert G
authors.initials: DG
authors.lastname: Gillespie
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Cuiling
authors.initials: C
authors.lastname: Xu
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stock
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Dongzhu
authors.initials: D
authors.lastname: Ma
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Policicchio
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Raehtz
authors.affiliation: Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Rinaldo
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Apetrei
authors.affiliation: Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.affiliation: Division of Infectious Diseases, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Bernard J C
authors.initials: BJ
authors.lastname: Macatangay
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA pandrea@pitt.edu.
authors.forename: Ivona
authors.initials: I
authors.lastname: Pandrea
mesh_terms: D015720:5'-Nucleotidase / Q000276:immunology*; D000241:Adenosine / Q000276:immunology*; D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D001081:Apyrase / Q000276:immunology*; D002522:Chlorocebus aethiops; D002908:Chronic Disease; D016207:Cytokines / Q000276:immunology; D018819:Dipeptidyl Peptidase 4 / Q000276:immunology*; D006801:Humans; D008254:Macaca nemestrina; D008297:Male; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000473:pathology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D015720:5'-Nucleotidase; D018819:Dipeptidyl Peptidase 4; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine