A compartmentalized type I interferon response in the gut during chronic HIV-1 infection is associated with immunopathogenesis. (31st July 2018)

• Record Type: Journal Article
• Authors: Dillon, Stephanie M.; Guo, Kejun; Austin, Gregory L.; Gianella, Sara; Engen, Phillip A.; Mutlu, Ece A.; Losurdo, John; Swanson, Garth; Chakradeo, Prachi; Keshavarzian, Ali; Landay, Alan L.; Santiago, Mario L.; Wilson, Cara C.
• Is Part Of: AIDS. Volume 32:Number 12(2018)
• Publication Date: 2018-07-31
• Subjects: gut -- HIV-1 infection -- interferon-stimulated genes -- inflammation -- mucosal immunology -- type I interferon; AIDS (Disease) -- Periodicals; Acquired Immunodeficiency Syndrome; AIDS (Disease); Periodicals; Periodicals; 616.9792005
• DOI: 10.1097/QAD.0000000000001863
• Languages: English
• ISSNs: 0269-9370

Abstract

Abstract : Objective(s): Type I interferon (IFN-I) responses confer both protective and pathogenic effects in persistent virus infections. IFN-I diversity, stage of infection and tissue compartment may account for this dichotomy. The gut is a major site of early HIV-1 replication and microbial translocation, but the nature of the IFN-I response in this compartment remains unclear. Design: Samples were obtained from two IRB-approved cross-sectional studies. The first study included individuals with chronic, untreated HIV-1 infection ( n = 24) and age/sex-balanced uninfected controls ( n = 14). The second study included antiretroviral-treated, HIV-1-infected individuals ( n = 15) and uninfected controls ( n = 15). Methods: The expression of 12 IFNα subtypes, IFNβ and antiviral IFN-stimulated genes (ISGs) were quantified in peripheral blood mononuclear cells (PBMCs) and colon biopsies using real-time PCR and next-generation sequencing. In untreated HIV-1-infected individuals, associations between IFN-I responses and gut HIV-1 RNA levels as well as previously established measures of colonic and systemic immunological indices were determined. Results: IFNα1, IFNα2, IFNα4, IFNα5 and IFNα8 were upregulated in PBMCs during untreated chronic HIV-1 infection, but IFNβ was undetectable. By contrast, IFNβ was upregulated and all IFNα subtypes were downregulated in gut tissue. Gut ISG levels positively correlated with gut HIV-1 RNA and immune activation, microbial translocation and inflammation markers. Gut IFN-I responses were not significantly different between HIV-1-infected individuals on antiretroviral treatment and uninfected controls. Conclusion: The IFN-I response is compartmentalized during chronic untreated HIV-1 infection, with IFNβ being more predominant in the gut. Gut IFN-I responses are associated with immunopathogenesis, and viral replication is likely a major driver of this response. Abstract : Supplemental Digital Content is available in the text