Exosomes derived from HIV-1-infected cells promote growth and progression of cancer via HIV TAR RNA

Lechuang Chen,Douglas Bazdar,Bingcheng Wang,Clifford V Harding,Hong Yue,Zhimin Feng,Jonathan Karn,Uri Mbonye,Ge Jin,Chad Zender,Scott F Sieg,Leslie Bruggeman

doi:10.1038/s41467-018-07006-2

Abstract

People living with HIV/AIDS on antiretroviral therapy have increased risk of non-AIDS-defining cancers (NADCs). However, the underlying mechanism for development and progression of certain NADCs remains obscure. Here we show that exosomes released from HIV-infected T cells and those purified from blood of HIV-positive patients stimulate proliferation, migration and invasion of oral/oropharyngeal and lung cancer cells. The HIV transactivation response (TAR) element RNA in HIV-infected T-cell exosomes is responsible for promoting cancer cell proliferation and inducing expression of proto-oncogenes and Toll-like receptor 3 (TLR3)-inducible genes. These effects depend on the loop/bulge region of the molecule. HIV-infected T-cell exosomes rapidly enter recipient cells through epidermal growth factor receptor (EGFR) and stimulate ERK1/2 phosphorylation via the EGFR/TLR3 axis. Thus, our findings indicate that TAR RNA-containing exosomes from HIV-infected T cells promote growth and progression of particular NADCs through activation of the ERK cascade in an EGFR/TLR3-dependent manner.

Highlights

People living with HIV/AIDS on antiretroviral therapy have increased risk of non-AIDSdefining cancers (NADCs)
J1.116, a latently HIV-1-infected human Jurkat T-cell line, 8E5/LAV17, a LAV-infected CD4+ human CEM T-cell line, and their respective non-HIV control lines Jurkat and CEM were cultured in media supplemented with fetal bovine serum (FBS) that was exosome depleted by ultracentrifugation at 100,000 × g for 16 h at 4 °C18
We find that exosomes released from HIV-1-infected T cells promote proliferation, migration, invasion, as well as proto-oncogene expression of head and neck squamous cell carcinoma (HNSCC) and lung cancer cells in vitro and stimulate xenograft tumor growth in vivo

Summary

Introduction

People living with HIV/AIDS on antiretroviral therapy have increased risk of non-AIDSdefining cancers (NADCs). The HIV transactivation response (TAR) element RNA in HIV-infected T-cell exosomes is responsible for promoting cancer cell proliferation and inducing expression of proto-oncogenes and Tolllike receptor 3 (TLR3)-inducible genes These effects depend on the loop/bulge region of the molecule. Recent epidemiological studies indicate that cancer risk is elevated among older people living with HIV; the excess absolute risks have increased with age for lung, oral cavity/pharyngeal, anal, and liver cancers[4] It remains unknown whether HIV-infected cells are involved in the development and progression of NADCs. Most types of cells can release membrane-enclosed vesicles, generally called extracellular vesicles (EVs), into the extracellular space for intercellular communication, molecular transfer, and immune regulation at local and distant sites[5]. Our data indicate that TAR RNA-bearing exosomes activate the ERK1/2 cascade in a b

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Conclusion