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* |
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Authors: | Yue Yin Shaoying Zhang Haihua Luo Xu Zhang Guannan Geng Jun Li Xuemin Guo Weiping Cai Linghua Li Chao Liu Hui Zhang |
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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 ;¶Department of Infectious Diseases, Guangzhou Eighth People''s Hospital, Guangzhou Medical University, Guangzhou 510080, China |
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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. |
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