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

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 IFN? subtypes, IFN? 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:IFN?1, IFN?2, IFN?4, IFN?5 and IFN?8 were upregulated in PBMCs during untreated chronic HIV-1 infection, but IFN? was undetectable. By contrast, IFN? was upregulated and all IFN? 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 IFN? 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.

SUBMITTER: Dillon SM 

PROVIDER: S-EPMC6054446 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature