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Sensing of HIV-1 by TLR8 activates human T cells and reverses latency.

ABSTRACT: During HIV infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood. Here we show that synthetic ligands of TLR8 boosted T cell receptor signaling, resulting in increased cytokine production and upregulation of surface activation markers. Adjuvant TLR8 stimulation, but not TLR7 or TLR9, further promoted T helper cell differentiation towards Th1 and Th17. In addition, we found that endosomal HIV induced cytokine secretion from CD4+ T cells in a TLR8-specific manner. TLR8 engagement also enhanced HIV-1 replication and potentiated the reversal of latency in patient-derived T cells. The adjuvant TLR8 activity in T cells can contribute to viral dissemination in the lymph node and low-grade inflammation in HIV patients. In addition, it can potentially be exploited for therapeutic targeting and vaccine development.

SUBMITTER: Meas HZ

PROVIDER: S-EPMC6952430 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Sensing of HIV-1 by TLR8 activates human T cells and reverses latency.

Meås Hany Zekaria HZ Haug Markus M Beckwith Marianne Sandvold MS Louet Claire C Ryan Liv L Hu Zhenyi Z Landskron Johannes J Nordbø Svein Arne SA Taskén Kjetil K Yin Hang H Damås Jan Kristian JK Flo Trude Helen TH

Nature communications 20200109 1

During HIV infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood. Here we show that synthetic ligands of TLR8 boosted T cell receptor signaling, resulting in increased cytokine production and upregulation of surf ...[more]

PMID: 31919342

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Project description:BackgroundNewborns display distinct immune responses that contribute to susceptibility to infection and reduced vaccine responses. Toll-like receptor (TLR) agonists may serve as vaccine adjuvants, when given individually or in combination, but responses of neonatal leukocytes to many TLR agonists are diminished. TLR8 agonists are more effective than other TLR agonists in activating human neonatal leukocytes in vitro, but little is known about whether different TLR8 agonists may distinctly activate neonatal leukocytes. We characterized the in vitro immuno-stimulatory activities of a novel benzazepine TLR8 agonist, VTX-294, in comparison to imidazoquinolines that activate TLR8 (R-848; (TLR7/8) CL075; (TLR8/7)), with respect to activation of human newborn and adult leukocytes. Effects of VTX-294 and R-848 in combination with monophosphoryl lipid A (MPLA; TLR4) were also assessed.MethodsTLR agonist specificity was assessed using TLR-transfected HEK293 cells expressing a NF-?B reporter gene. TLR agonist-induced cytokine production was measured in human newborn cord and adult peripheral blood using ELISA and multiplex assays. Newborn and adult monocytes were differentiated into monocyte-derived dendritic cells (MoDCs) and TLR agonist-induced activation assessed by cytokine production (ELISA) and co-stimulatory molecule expression (flow cytometry).ResultsVTX-294 was ? 100x more active on TLR8- than TLR7-transfected HEK cells (EC50, ? 50 nM vs. ? 5700 nM). VTX-294-induced TNF and IL-1? production were comparable in newborn cord and adult peripheral blood, while VTX-294 was 1 log more potent in inducing TNF and IL-1? production than MPLA, R848 or CL075. Combination of VTX-294 and MPLA induced greater blood TNF and IL-1? responses than combination of R-848 and MPLA. VTX-294 also potently induced expression of cytokines and co-stimulatory molecules HLA-DR and CD86 in human newborn MoDCs.ConclusionsVTX-294 is a novel ultra-potent TLR8 agonist that activates newborn and adult leukocytes and is a candidate vaccine adjuvant in both early life and adulthood.

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Sensing of HIV-1 by TLR8 activates human T cells and reverses latency.

Publications

Sensing of HIV-1 by TLR8 activates human T cells and reverses latency.

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