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

Hany Zekaria Meås,Claire Louet,Trude Helen Flo,Kjetil Taskén,Marianne Sandvold Beckwith,Markus Haug,Hang Yin,Jan Kristian Damås,Johannes Landskron,Svein Arne Nordbø,Liv Ryan,Zhenyi Hu

doi:10.1038/s41467-019-13837-4

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.

Highlights

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)
Activated CD4+ T cells were co-cultured for 3 h with donor HeLa or HEK293T cells expressing the X4 human immunodeficiency virus type 1 (HIV-1)-GagiGFP, human monocyte-derived macrophages (MDMs) infected with R5 HIV-1-Gag-iGFP or donor CD4+ T cells infected with X4-Gag-iGFP in the presence of the CXCR4 inhibitor AMD3100 or the CCR5 inhibitor Maraviroc, to prevent co-receptor mediated HIV-1 fusion
We further utilized flow cytometry to quantify the frequency of CD4+ T cells harboring intracellular HIV-1 (Fig. 1c and Supplementary Fig. 1c), which decreased over time when fusion was inhibited by AMD3100 (Fig. 1c)

Summary

Introduction

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). The adjuvant TLR8 activity in T cells can contribute to viral dissemination in the lymph node and low-grade inflammation in HIV patients. It can potentially be exploited for therapeutic targeting and vaccine development. It is currently not clear to what extent HIV-1 activates CD4+ T cell PRRs during the various stages of infection, and how this would impact infection In this situation, the local cytokine environment may well be shaped by T cells and act in an autocrine/paracrine manner. Ten functional TLRs have been discovered in humans of which

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Results

Conclusion