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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

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

Dillon Stephanie M SM Guo Kejun K Austin Gregory L GL Gianella Sara S Engen Phillip A PA Mutlu Ece A EA Losurdo John J Swanson Garth G Chakradeo Prachi P Keshavarzian Ali A Landay Alan L AL Santiago Mario L ML Wilson Cara C CC

AIDS (London, England) 20180701 12

<h4>Objective(s)</h4>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.<h4>Design</h4>Samples were obtained from two IRB-approved cross-sectional studies. The first study included individuals ...[more]

PMID: 29762170

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Project description:Humoral immune perturbations contribute to pathogenic outcomes in persons with HIV-1 infection (PWH). Gut barrier dysfunction in PWH is associated with microbial translocation and alterations in microbial communities (dysbiosis), and IgA, the most abundant immunoglobulin (Ig) isotype in the gut, is involved in gut homeostasis by interacting with the microbiome. We determined the impact of HIV-1 infection on the antibody repertoire in the gastrointestinal tract by comparing Ig gene utilization and somatic hypermutation (SHM) in colon biopsies from PWH (n = 19) versus age and sex-matched controls (n = 13). We correlated these Ig parameters with clinical, immunological, microbiome and virological data. Gene signatures of enhanced B cell activation were accompanied by skewed frequencies of multiple Ig Variable genes in PWH. PWH showed decreased frequencies of SHM in IgA and possibly IgG, with a substantial loss of highly mutated IgA sequences. The decline in IgA SHM in PWH correlated with gut CD4+ T cell loss and inversely correlated with mucosal inflammation and microbial translocation. Diminished gut IgA SHM in PWH was driven by transversion mutations at A or T deoxynucleotides, suggesting a defect not at the AID/APOBEC3 deamination step but at later stages of IgA SHM. These results expand our understanding of humoral immune perturbations in PWH that could have important implications in understanding mucosal immune defects in individuals with chronic HIV-1 infection. IMPORTANCE The gut is a major site of early HIV-1 replication and pathogenesis. Extensive CD4+ T cell depletion in this compartment results in a compromised epithelial barrier that facilitates the translocation of microbes into the underlying lamina propria and systemic circulation, resulting in chronic immune activation. To date, the consequences of microbial translocation on the mucosal humoral immune response (or vice versa) remains poorly integrated into the panoply of mucosal immune defects in PWH. We utilized next-generation sequencing approaches to profile the Ab repertoire and ascertain frequencies of somatic hypermutation in colon biopsies from antiretroviral therapy-naive PWH versus controls. Our findings identify perturbations in the Ab repertoire of PWH that could contribute to development or maintenance of dysbiosis. Moreover, IgA mutations significantly decreased in PWH and this was associated with adverse clinical outcomes. These data may provide insight into the mechanisms underlying impaired Ab-dependent gut homeostasis during chronic HIV-1 infection.

Dataset Information

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

Publications

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

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