A compartmentalized type I interferon response in the gut during chronic HIV-1 infection is associated with immunopathogenesis

Stephanie M. Dillon, Kejun Guo, Gregory L. Austin, Sara Gianella, Phillip A. Engen, Ece A. Mutlu, John Losurdo, Garth Swanson, Prachi Chakradeo, Ali Keshavarzian, Alan L. Landay, Mario L. Santiago, Cara C. Wilson

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 IFNa subtypes, IFNbandantiviral IFN-stimulatedgenes (ISGs) were quantified in peripheral blood mononuclear cells (PBMCs) and colon biopsies using real-time PCR and next-generation sequencing. In untreated HIV-1infected individuals, associations between IFN-I responses and gut HIV-1 RNA levels as well aspreviously 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 IFNb 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 individualson antiretroviral treatmentand 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.

Original languageEnglish (US)
Pages (from-to)1599-1611
Number of pages13
JournalAIDS
Volume32
Issue number12
DOIs
StatePublished - 2018
Externally publishedYes

Keywords

  • Gut
  • HIV-1 infection
  • Inflammation
  • Interferon-stimulated genes
  • Mucosal immunology
  • Type I interferon

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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