title: HIV-1 Infection-Induced Suppression of the Let-7i/IL-2 Axis Contributes to CD4(+) T Cell Death.
abstract: The mechanisms underlying HIV-1-mediated CD4(+) T cell depletion are highly complicated. Interleukin-2 (IL-2) is a key cytokine that maintains the survival and proliferation of activated CD4(+) T cells. IL-2 levels are disturbed during HIV-1 infection, but the underlying mechanism(s) requires further investigation. We have reported that cellular microRNA (miRNA) let-7i upregulates IL-2 expression by targeting the promoter TATA-box region, which functions as a positive regulator. In this study, we found that HIV-1 infection decreases the expression of let-7i in CD4(+) T cells by attenuating its promoter activity. The reduced let-7i miRNA expression led to a decline in IL-2 levels. A let-7i mimic increased IL-2 expression and subsequently enhanced the resistance of CD4(+) T cells to HIV-1-induced apoptosis. By contrast, the blockage of let-7i with a specific inhibitor resulted in elevated CD4(+) T cell apoptosis during HIV-1 infection. Furthermore, by knocking down the expression of IL-2, we found that the let-7i-mediated CD4(+) T cell resistance to apoptosis during HIV-1 infection was dependent on IL-2 signaling rather than an alternative CD95-mediated cell-death pathway. Taken together, our findings reveal a novel pathway for HIV-1-induced dysregulation of IL-2 cytokines and depletion of CD4(+) T-lymphocytes.
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.|Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.|Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.|Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
authors.forename: Shaoying
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.|Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
authors.forename: Haihua
authors.initials: H
authors.lastname: Luo
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.|Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation; D057809:HEK293 Cells; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000821:virology*; D035683:MicroRNAs / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C508594:IL2 protein, human; D007376:Interleukin-2; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human