title: Species-specific differences in the expression and regulation of α4β7 integrin in various nonhuman primates.
abstract: Among nonhuman primates, SIV-infected Asian pigtailed macaques (PM) are relatively more susceptible to infection and disease progression than SIV-infected rhesus macaques (RM). In addition, SIV-infected African natural hosts such as the sooty mangabeys (SM) are resistant to disease. The mechanisms associated with such species-related variable clinical outcomes remain ill-defined but hold the potential to provide insights into the underlying mechanisms surrounding HIV pathogenesis. Recent findings indicate that the expression of the heterodimeric gut homing integrin α4β7 can influence both susceptibility and disease progression in RM. It was reasoned that differences in the frequencies/surface densities of α4β7-expressing lymphocytes might contribute to the differences in the clinical outcome of SIV infection among NHPs. In this article, we report that CD4(+) T cells from PM constitutively express significantly higher levels of α4β7 than RM or SM. Retinoic acid, a key regulator of α4β7 expression, was paradoxically found at higher levels in the plasma of SM versus RM or PM. We also observed pairing of β7 with αE (αEβ7) on CD4(+) T cells in the peripheral blood of SM, but not PM or RM. Finally, the differential mean density of expression of α4β7 in RM versus SM versus PM was predominantly dictated by species-specific sequence differences at the level of the β7 promoters, as determined by in vitro reporter/promoter construct transfection studies. We propose that differences in the regulation and expression of α4β7 may explain, in part, the differences in susceptibility and SIV disease progression in these NHP models.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Siddappa N
authors.identifier: http://orcid.org/0000-0002-7423-1763
authors.initials: SN
authors.lastname: Byrareddy
authors.affiliation: Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Neil
authors.initials: N
authors.lastname: Sidell
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: James
authors.initials: J
authors.lastname: Arthos
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Claudia
authors.initials: C
authors.lastname: Cicala
authors.affiliation: Division of Microbiology and Immunology, Yerkes National Primate Center, Atlanta, GA 30329;
authors.forename: Chunxia
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Little
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Paul
authors.initials: P
authors.lastname: Dunbar
authors.affiliation: Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Gui X
authors.initials: GX
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, University of Maryland, Baltimore, MD 21201;
authors.forename: Keely
authors.initials: K
authors.lastname: Pierzchalski
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, University of Maryland, Baltimore, MD 21201;
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Kane
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Ann E
authors.initials: AE
authors.lastname: Mayne
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616; and.
authors.forename: Byeongwoon
authors.initials: B
authors.lastname: Song
authors.affiliation: Laboratory of Human Virology, Federal University of Rio de Janeiro, 20231-050 Rio de Janeiro, Brazil.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Soares
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322; Division of Microbiology and Immunology, Yerkes National Primate Center, Atlanta, GA 30329;
authors.forename: Francois
authors.initials: F
authors.lastname: Villinger
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Fauci
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322; pathaaa@emory.edu.
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
mesh_terms: D000818:Animals; D001665:Binding Sites; D001773:Blood Cells / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016665:Cercocebus atys; D003001:Cloning, Molecular; D015870:Gene Expression; D017930:Genes, Reporter; D016130:Immunophenotyping; D016023:Integrins / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008251:Macaca; D008969:Molecular Sequence Data; D010802:Phylogeny; D011323:Primates; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000235:genetics; D017422:Sequence Analysis, DNA; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology; D013045:Species Specificity; D014157:Transcription Factors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000097:blood; D014212:Tretinoin / Q000097:blood / Q000378:metabolism
chemical_list: D016023:Integrins; D019713:Receptors, CCR5; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C071777:integrin alpha4beta7; D014212:Tretinoin