TLR agonists enhance responsiveness of inflammatory innate immune cells in HLA-B*57-positive HIV patients
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ORIGINAL ARTICLE
TLR agonists enhance responsiveness of inflammatory innate immune cells in HLA-B*57-positive HIV patients L. Dold 1,2 & L. Zimmer 1 & C. Schwarze-Zander 1,2 & C. Boesecke 1,2 & R. Mohr 1,2 & J.-C. Wasmuth 1,2 & K. Ommer 3 & B. Gathof 3 & B. Krämer 1 & J. Nattermann 1,2 & C. P. Strassburg 1,2 & J. K. Rockstroh 1,2 & U. Spengler 1 & B. Langhans 1,2 Received: 15 July 2020 / Revised: 15 October 2020 / Accepted: 19 October 2020 # The Author(s) 2020
Abstract HLA-B*57 affects the course of HIV infection. Under antiretroviral therapy, its effects cannot be explained by outstandingly efficient T cell responses alone but may also involve cells of innate immunity. Studying in vitro stimulation with Pam3CSK4, E. coli LPS-B5 and CpG-ODN-2216, we observed greater induction of IL-6/IL-1beta double-positive CD14+CD16++ monocytes as well as IFN-gamma-positive cytotoxic CD56highCD16neg NK cells in HLA-B*57- versus HLA-B*44-positive HIV patients, while TNF-alpha induction remained unchanged. Differences were not seen in the other monocyte and NK cell subsets or in HLAmatched healthy controls. Our findings show that, in virally suppressed HIV infection, HLA-B*57 is associated with enhanced responsiveness of inflammatory innate immune cells to TLR ligands, possibly contributing to increased vulnerability in sepsis. Key messages • HLA-B*57 is a host factor affecting clinical outcomes of HIV infection. • HLA-B*57 modifies inflammatory subsets of NK cells and monocytes in HIV infection. • In HLA-B*57-positive HIV patients TLR agonists induce enhanced IL-6/IL-1beta in monocytes. • NK cells from HLA-B*57 HIV patients release more IFN-gamma upon TLR costimulation. • HLA-B*57 is linked to enhanced inflammatory responsiveness to TLR ligands. Keywords HIV . HLA-B*57 . cART . Bacterial infections . Toll-like receptor stimulation . Inflammatory immune response
Introduction The course of human immunodeficiency virus (HIV) infection is highly variably owing to complex interactions between the virus and the host. Among multiple factors HLA class I loci have been identified as pivotal host factors affecting clinical outcomes. In particular, HLA-B*57 appears to be linked with
U. Spengler and B. Langhans contributed equally to this work. * B. Langhans [email protected] 1
Department of Internal Medicine I, University Hospital of Bonn (UKB), Venusberg-Campus 1, 53127 Bonn, Germany
2
German Center for Infection Research (DZIF), Partner Site Cologne-Bonn, Bonn, Germany
3
Institute of Transfusion Medicine, University Hospital of Cologne, Cologne, Germany
low level viremia and delayed disease progression, which has been attributed to an exceptional efficacy of HLA-B*57-restricted T cells to control HIV infection [1]. While this protective effect was consistently observed in untreated HIV patients, even across different HLA-B*57 subtypes and diverse HIV strains [2], the risk to die from bacterial infection and sepsis was unexpectedly found to be substantially increased in HLA-B*57-positive patients, whose HIV replication wa
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