title: Differential regulation of the Let-7 family of microRNAs in CD4+ T cells alters IL-10 expression.
abstract: MicroRNAs (miRNAs) are ∼22-nt small RNAs that are important regulators of mRNA turnover and translation. Recent studies have shown the importance of the miRNA pathway in HIV-1 infection, particularly in maintaining latency. Our initial in vitro studies demonstrated that HIV-1-infected HUT78 cells expressed significantly higher IL-10 levels compared with uninfected cultures. IL-10 plays an important role in the dysregulated cytotoxic T cell response to HIV-1, and in silico algorithms suggested that let-7 miRNAs target IL10 mRNA. In a time course experiment, we demonstrated that let-7 miRNAs fall rapidly following HIV-1 infection in HUT78 cells with concomitant rises in IL-10. To show a direct link between let-7 and IL-10, forced overexpression of let-7 miRNAs resulted in significantly reduced IL-10 levels, whereas inhibition of the function of these miRNAs increased IL-10. To demonstrate the relevance of these results, we focused our attention on CD4(+) T cells from uninfected healthy controls, chronic HIV-1-infected patients, and long-term nonprogressors. We characterized miRNA changes in CD4(+) T cells from these three groups and demonstrated that let-7 miRNAs were highly expressed in CD4(+) T cells from healthy controls and let-7 miRNAs were significantly decreased in chronic HIV-1 infected compared with both healthy controls and long-term nonprogressors. We describe a novel mechanism whereby IL-10 levels can be potentially modulated by changes to let-7 miRNAs. In HIV-1 infection, the decrease in let-7 miRNAs may result in an increase in IL-10 from CD4(+) T cells and provide the virus with an important survival advantage by manipulating the host immune response.
authors.affiliation: Immunovirology Laboratory, St. Vincent's Centre for Applied Medical Research, Darlinghurst, New South Wales 2010, Australia. s.swaminathan@amr.org.au
authors.forename: Sanjay
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Kazuo
authors.initials: K
authors.lastname: Suzuki
authors.forename: Nabila
authors.initials: N
authors.lastname: Seddiki
authors.forename: Warren
authors.initials: W
authors.lastname: Kaplan
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cowley
authors.forename: Chantelle L
authors.initials: CL
authors.lastname: Hood
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Clancy
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Murray
authors.forename: Catalina
authors.initials: C
authors.lastname: Méndez
authors.forename: Linda
authors.initials: L
authors.lastname: Gelgor
authors.forename: Ben
authors.initials: B
authors.lastname: Anderson
authors.forename: Norman
authors.initials: N
authors.lastname: Roth
authors.forename: David A
authors.initials: DA
authors.lastname: Cooper
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kelleher
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics* / Q000276:immunology; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000032:analysis / Q000096:biosynthesis* / Q000276:immunology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; C487931:mirnlet7 microRNA, human; D016753:Interleukin-10