Abstract 5060: Exosomes derived from HIV-infected T cells promote cancer cell growth and progression via the HIV TAR RNA

Abstract

Abstract Background: Residual and persistent HIV replication plays key roles in the development and progression of non-AIDS-defining cancers (NADCs), including head and neck as well as lung cancers. However, the underlying mechanisms remain elusive. HIV-infected T cells produce immunologically active exosomes to influence intercellular communication and regulate immune response at both local and distant sites, thus potentially contribute to enhanced risk for tumorigenesis. We investigated the role of exosomes derived from HIV-infected T cells in growth and progression of head and neck cancer (HNC) and lung cancer cells. Methods: Exosomes were isolated from conditioned media of HIV-1-infected J1.1 cells and non-infected control Jurkat cells using the ultracentrifugation protocol. Exosomes were validated by western blotting for tetraspanins (CD9, CD63 and CD81) and transmission electron microscope. The acetyl-CoA acetylcholinesterase (AChE) enzyme activity was used to quantify exosomes. HNC cells UM-SCC-104, TR146, HSC3, SCC9 and lung cancer cells NCI-H1299, NCI-H1437 were treated with exosomes for cell growth, migration and gene expression in vitro and in vivo. Exosome HIV RNA was determined by quantitative RT-PCR. Results: Exosomes isolated from HIV-1-infected T cells, but not those from normal control T cells, significantly stimulated HNC and lung cancer cell proliferation, migration and invasion in vitro. Exosomes purified from plasma of HIV-positive individuals also stimulated proliferation of cancer cells. HNC and lung cancer cells co-inoculation with exosomes from HIV-1-infected T cells into nude mice promoted tumor growth compared to those from non-HIV control T cells. Mechanistically, we found that the HIV trans-activation response (TAR) element RNA, which exists in excess of other HIV RNAs in exosomes from HIV-1-infected T cells, enhanced cancer cell proliferation and stimulated EGF- and TLR3-inducible gene expression. The TAR RNA mutant with nucleotide replacements in the loop/bulge region failed to induce gene expression. Moreover, co-transfection of the TAR RNA aptamer blocked induction of gene expression induced by HIV-positive T-cell exosomes. Conclusion: HIV TAR RNA-containing exosomes derived from HIV-1-infected T cells promote growth and progression of NADCs through interaction with EGFR and TLR3. Citation Format: Lechuang chen, Zhimin Feng, Hong Yue, Scott Sieg, Bingcheng Wang, Alex Y. Huang, Ge Jin. Exosomes derived from HIV-infected T cells promote cancer cell growth and progression via the HIV TAR RNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5060.