title: Host factor transcriptional regulation contributes to preferential expression of HIV type 1 in IL-4-producing CD4 T cells.
abstract: HIV type 1 (HIV-1) replicates preferentially in IL-4-producing CD4 T cells for unclear reasons. We show increased HIV-1 expression is irrespective of viral tropism for chemokine receptors as previously suggested, but rather transcription of the HIV-1 long terminal repeat (LTR) is increased in IL-4-producing CD4 T cells. Increased expression of HIV-1 message is also confirmed in IL-4-producing CD4 T cells from HIV-1-infected individuals ex vivo. In exploring a transcriptional mechanism, we identify a novel c-maf (required for IL-4 expression) transcription factor binding site just upstream of the dual NF-κB/NFAT binding sites in the proximal HIV-1 LTR. We demonstrate that c-maf binds this site in vivo and synergistically augments HIV-1 transcription in cooperation with NFAT2 and NF-κB p65, but not NFAT1 or NF-κB p50. Conversely, small interfering RNA inhibition of c-maf reduces HIV-1 transcription in IL-4-producing T cells. Thus, c-maf increases HIV-1 expression in IL-4-producing CD4 T cells by binding the proximal HIV-1 LTR and augmenting HIV-1 transcription in partnership with NFAT2 and NF-κB p65 specifically. This has important implications for selective targeting of transcription factors during HIV-1 infection because, over the course of HIV-1 progression/AIDS, IL-4-producing T cells frequently predominate and substantially contribute to disease pathology.
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Mingce
authors.initials: M
authors.lastname: Zhang
authors.forename: Adrian
authors.initials: A
authors.lastname: Clausell
authors.forename: Tanya
authors.initials: T
authors.lastname: Robinson
authors.forename: Jiyi
authors.initials: J
authors.lastname: Yin
authors.forename: Eric
authors.initials: E
authors.lastname: Chen
authors.forename: Leanne
authors.initials: L
authors.lastname: Johnson
authors.forename: Greta
authors.initials: G
authors.lastname: Weiss
authors.forename: Steffanie
authors.initials: S
authors.lastname: Sabbaj
authors.forename: Robert M
authors.initials: RM
authors.lastname: Lowe
authors.forename: Fred H
authors.initials: FH
authors.lastname: Wagner
authors.forename: Paul A
authors.initials: PA
authors.lastname: Goepfert
authors.forename: Olaf
authors.initials: O
authors.lastname: Kutsch
authors.forename: Randy Q
authors.initials: RQ
authors.lastname: Cron
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D006801:Humans; D015847:Interleukin-4 / Q000096:biosynthesis*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D051257:Proto-Oncogene Proteins c-maf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology; D017735:Virus Latency / Q000276:immunology; D014779:Virus Replication / Q000276:immunology*
chemical_list: C508598:IL4 protein, human; C495607:MAF protein, human; D051257:Proto-Oncogene Proteins c-maf; D015847:Interleukin-4