title: Increased expression of negative regulators of cytokine signaling during chronic HIV disease cause functionally exhausted state of dendritic cells.
abstract: Mechanisms of functional impairment of dendritic cells (DCs) during chronic HIV-1 infection are not well understood. In order to understand this phenomenon, we aimed to study the expression of negative regulators of cytokine signaling and correlate with DC exhaustion during chronic HIV-1 disease. Monocyte-derived DCs (mo-DCs) from 27 HIV-1 infected patients (CD4+ T-cell counts: 429±44 cells/μL, plasma viral load: Log103.9±1.0copies/ml) and 19 healthy controls (HCs) were stimulated ex vivo with TLR4 agonist, lipopolysaccharide (LPS) for 2days to evaluate their functional fitness. The expression of a set of genes associated with cytokine signaling was evaluated in a custom designed PCR array by Real-Time PCR. The mo-DCs from HIV-1 infected patients depicted functional exhaustion as evident by decreased allo-stimulation index (mean±SD: 10±6 vs. 24±16) (p<0.05), decreased cytokine production (pg/ml) (IL-12: 4.6±16 vs. 25±85; TNF-α: 128±279 vs. 286±544; IL-10: 6±12 vs. 13±20; IL-8: 10,688±11,748 vs. 17,470±125,049) and retained endocytosis (1.1±0.3 vs. 1.0±0.29) (p<0.05) even after LPS-stimulation, as compared to HCs. Significantly upregulated expression of SOCS-1 (mean±SD fold change: 2.2±2vs.0.8±0.6), SOCS-3 (6.3±7.4vs.1.4±0.4), PIAS-1 (1.6±0.1vs.1.0±0.3) and SHP-1 (0.8±0.4vs.0.4±0.2) correlated positively with PD-L1 expression in these DCs (Spearman's coefficient, SOCS-1: 0.63, SOCS-3: 1.0 and PIAS-1: 0.7) (p<0.05). The expression of these molecules trended positively with plasma viral load and negatively with CD4+ T-cell counts. These findings suggest that the upregulation of negative regulatory factors during chronic HIV disease have profound down-modulatory effects on DC functions and establishment of an overall exhausted state. Understanding mechanisms causing upregulation of these factors may lead to the design of new generation therapeutics based on silencing of their gene expression.
authors.affiliation: Department of Immunopathology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Sachdeva
authors.affiliation: Department of Internal Medicine, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
authors.forename: Aman
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Immunopathology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. Electronic address: arora.sunil@pgimer.edu.in.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Arora
mesh_terms: D000328:Adult; D002908:Chronic Disease; D016207:Cytokines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides
keywords: Dendritic cells; Exhaustion; HIV; Negative regulators of cytokine signaling