Host Factor Transcriptional Regulation Contributes to Preferential Expression of HIV-1 in IL-4 Producing CD4 T Cells

• Published in: The Journal of immunology (1950) 2012-08, Vol.189 (6), p.2746-2757
• Main Authors: Zhang, Mingce, Clausell, Adrian, Robinson, Tanya, Yin, Jiyi, Chen, Eric, Johnson, Leanne, Weiss, Greta, Sabbaj, Steffanie, Lowe, Robert M., Wagner, Fred H., Goepfert, Paul A., Kutsch, Olaf, Cron, Randy Q.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1103129

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 NFκB/NFAT binding sites in the proximal HIV-1 LTR. We demonstrate c-maf binds this site in vivo and synergistically augments HIV-1 transcription in cooperation with NFAT2 and NFκB p65, but not NFAT1 nor NFκB p50. Conversely, siRNA 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 NFκB p65, specifically. This has important implications for selective targeting of transcription factors during HIV-1 infection since, over the course of HIV-1 progression/AIDS, IL-4 producing T cells frequently predominate and substantially contribute to disease pathology.