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

• Published in: Nature communications Vol. 11; no. 1; p. 147
• Main Authors: Meås, Hany Zekaria, Haug, Markus, Beckwith, Marianne Sandvold, Louet, Claire, Ryan, Liv, Hu, Zhenyi, Landskron, Johannes, Nordbø, Svein Arne, Taskén, Kjetil, Yin, Hang, Damås, Jan Kristian, Flo, Trude Helen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/109; 13/21; 13/31; 14; 14/19; 38; 38/77; 631/250; 631/250/2152; 631/80; 631/80/304; 631/80/86; 96; CD4 antigen; Cell differentiation; Cell Line; Cytokines; Differentiation (biology); Disease transmission; Genomes; Helper cells; HIV; HIV Infections - immunology; HIV Infections - transmission; HIV-1 - immunology; Human immunodeficiency virus; Humanities and Social Sciences; Humans; Immune system; Immunity, Innate - immunology; Inflammation; Inflammatory response; Latency; Lymph nodes; Lymphocytes; Lymphocytes T; multidisciplinary; Proteins; Receptors; Replication; Science; Science (multidisciplinary); Signal Transduction - immunology; Stimulation; Surface activation; T cell receptors; Th1 Cells - immunology; Th17 Cells - immunology; Therapeutic targets; TLR7 protein; TLR9 protein; Toll-Like Receptor 8 - immunology; Toll-Like Receptor 8 - metabolism; Toll-like receptors; Vaccine development; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13837-4

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. Manipulation of Toll-like receptors (TLRs) affects HIV-1 infection and latency reversal. Here, the authors show that HIV-1 is endocytosed and recognized by TLR8 in human primary CD4+T cells and that TLR8 stimulation induces an inflammatory response that promotes HIV-1 replication and reversal of latency.