title: Interleukin 7 up-regulates CD95 protein on CD4+ T cells by affecting mRNA alternative splicing: priming for a synergistic effect on HIV-1 reservoir maintenance.
abstract: Interleukin-7 (IL-7) has been used as an immunoregulatory and latency-reversing agent in human immunodeficiency virus type 1 (HIV-1) infection. Although IL-7 can restore circulating CD4(+) T cell counts in HIV-1-infected patients, the anti-apoptotic and proliferative effects of IL-7 appear to benefit survival and expansion of HIV-1-latently infected memory CD4(+) T lymphocytes. IL-7 has been shown to elevate CD95 on CD4(+) T cells in HIV-1-infected individuals and prime CD4(+) T lymphocytes to CD95-mediated proliferative or apoptotic signals. Here we observed that through increasing microRNA-124, IL-7 down-regulates the splicing regulator polypyrimidine tract binding protein (PTB), leading to inclusion of the transmembrane domain-encoding exon 6 of CD95 mRNA and, subsequently, elevation of CD95 on memory CD4(+) T cells. Moreover, IL-7 up-regulates cellular FLICE-like inhibitory protein (c-FLIP) and stimulates c-Jun N-terminal kinase (JNK) phosphorylation, which switches CD95 signaling to survival mode in memory CD4(+) T lymphocytes. As a result, co-stimulation through IL-7/IL-7R and FasL/CD95 signal pathways augments IL-7-mediated survival and expansion of HIV-1-latently infected memory CD4(+) T lymphocytes. Collectively, we have demonstrated a novel mechanism for IL-7-mediated maintenance of HIV-1 reservoir.
authors.affiliation: From the Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China and.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yin
authors.affiliation: From the Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China and.
authors.forename: Shaoying
authors.initials: S
authors.lastname: Zhang
authors.affiliation: From the Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China and.
authors.forename: Haihua
authors.initials: H
authors.lastname: Luo
authors.affiliation: From the Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China and.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China and.
authors.forename: Guannan
authors.initials: G
authors.lastname: Geng
authors.affiliation: From the Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China and.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: From the Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China and.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou 510080, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Cai
authors.affiliation: Department of Infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou 510080, China.
authors.forename: Linghua
authors.initials: L
authors.lastname: Li
authors.affiliation: From the Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China and liuchao9@mail.sysu.edu.cn.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: From the Institute of Human Virology and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China and zhangh92@mail.sysu.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
mesh_terms: D017398:Alternative Splicing; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D049109:Cell Proliferation; D002470:Cell Survival; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D007156:Immunologic Memory; D015851:Interleukin-7 / Q000235:genetics* / Q000276:immunology; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D008969:Molecular Sequence Data; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics* / Q000276:immunology; D061251:Primary Cell Culture; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D019562:Viral Load; D014779:Virus Replication; D019014:fas Receptor / Q000235:genetics* / Q000276:immunology
chemical_list: C491901:FAS protein, human; D015851:Interleukin-7; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D020395:Receptors, Interleukin-7; D019014:fas Receptor; D038941:Polypyrimidine Tract-Binding Protein
keywords: Alternative Splicing; CD95; Human Immunodeficiency Virus (HIV); Interleukin; MicroRNA (miRNA); PTB; Post-transcriptional Regulation