The Myeloid-Specific Transcription Factor PU.1 Upregulates Mannose Receptor Expression but Represses Basal Activity of the HIV-LTR Promoter.

Sandra Kao, Eri Miyagi, Rosa Mallorson, Hideki Saito, Sayaka Sukegawa, Abhik Mukherji, Allyson Mateja, Damien Ferhadian, Helena Fabryova, Kathleen Clouse, Klaus Strebel

Journal of virology 2022 Jul 27

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Human mannose receptor 1 (MRC1) is a cell surface receptor expressed in macrophages and other myeloid cells that inhibits human immunodeficiency virus type 1 (HIV-1) particle release by tethering virions to producer cell membranes. HIV-1 counteracts MRC1 expression by inhibiting mrc1 transcription. Here, we investigated the mechanism of MRC1 downregulation in HIV-1-infected macrophages. We identified the myeloid cell-specific transcription factor PU.1 as critical for regulating MRC1 expression. In the course of our study, we recognized a complex interplay between HIV-1 Tat and PU.1 transcription factors: Tat upregulated HIV-1 gene expression but inhibited mrc1 transcription, whereas PU.1 inhibited HIV-1 transcription but activated MRC1 expression. Disturbing this equilibrium by silencing PU.1 resulted in increased HIV-1 gene expression and reduced MRC1 promoter activity. Our study identified PU.1 as a central player in transcriptional control, regulating a complex interplay between viral and host gene expression in HIV-infected macrophages. IMPORTANCE HIV-1 replication in primary human cells depends on the activity of virus-encoded proteins but also involves cellular factors that can either promote (viral dependency factors) or inhibit (host restriction factors) virus replication. In previous work, we identified human MRC1 as a macrophage-specific host restriction factor that inhibits the detachment of viral particles from infected cells. Here, we report that HIV-1 counteracts this effect of MRC1 by imposing a transcriptional block on cellular MRC1 gene expression. The transcriptional inhibition of the MRC1 gene is accomplished by Tat, an HIV-1 factor whose best-described function actually is the enhancement of HIV-1 gene expression. Thus, HIV-1 has evolved to use the same protein for (i) activation of its own gene expression while (ii) inhibiting expression of MRC1 and other host factors.

Citation

Sandra Kao, Eri Miyagi, Rosa Mallorson, Hideki Saito, Sayaka Sukegawa, Abhik Mukherji, Allyson Mateja, Damien Ferhadian, Helena Fabryova, Kathleen Clouse, Klaus Strebel. The Myeloid-Specific Transcription Factor PU.1 Upregulates Mannose Receptor Expression but Represses Basal Activity of the HIV-LTR Promoter. Journal of virology. 2022 Jul 27;96(14):e0065222