Species-Specific Differences in the Expression and Regulation of alpha 4 beta 7 Integrin in Various Nonhuman Primates

• Published in: The Journal of immunology (1950) 2015-06, Vol.194 (12), p.5968-5979
• Main Authors: Byrareddy, Siddappa N, Sidell, Neil, Arthos, James, Cicala, Claudia, Zhao, Chunxia, Little, Dawn M, Dunbar, Paul, Yang, Gui X, Pierzchalski, Keely, Kane, Maureen A, Mayne, Ann E, Song, Byeongwoon, Soares, Marcelo A, Villinger, Francois, Fauci, Anthony S, Ansari, Aftab A
• Format: Article
• Language: English
• Subjects: Human immunodeficiency virus; Macaca mulatta; Simian immunodeficiency virus
• ISSN: 0022-1767
• DOI: 10.4049/jimmunol.1402866

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 alpha 4 beta 7 can influence both susceptibility and disease progression in RM. It was reasoned that differences in the frequencies/surface densities of alpha 4 beta 7-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 alpha 4 beta 7 than RM or SM. Retinoic acid, a key regulator of alpha 4 beta 7 expression, was paradoxically found at higher levels in the plasma of SM versus RM or PM. We also observed pairing of beta 7 with alpha E ( alpha E beta 7) on CD4+ T cells in the peripheral blood of SM, but not PM or RM. Finally, the differential mean density of expression of alpha 4 beta 7 in RM versus SM versus PM was predominantly dictated by species-specific sequence differences at the level of the beta 7 promoters, as determined by in vitro reporter/promoter construct transfection studies. We propose that differences in the regulation and expression of alpha 4 beta 7 may explain, in part, the differences in susceptibility and SIV disease progression in these NHP models.