Altered recruitment of Sp isoforms to HIV-1 long terminal repeat between differentiated monoblastic cell lines and primary monocyte-derived macrophages

Abstract

Human immunodeficiency virus type 1 (HIV-1) transcription in cells of the monocyte-macrophage lineage is regulated by interactions between the HIV-1 long terminal repeat (LTR) and a variety of host cell and viral proteins. Binding of the Sp family of transcription factors (TFs) to the G/C box array of the LTR governs both basal as well as activated LTR-directed transcriptional activity. The effect of monocytic differentiation on Sp factor binding and transactivation was examined with respect to the HIV-1 LTR. The binding of Sp1, full-length Sp3 and truncated Sp3 to a high affinity HIV-1 Sp element was specifically investigated and results showed that Sp1 binding increased relative to the binding of the sum of full-length and truncated Sp3 binding following chemically-induced monocytic differentiation in monoblastic (U-937, THP-1) and myelomonocytic (HL-60) cells. In addition, Sp binding ratios from PMA-induced cell lines were shown to more closely approximate those derived from primary monocyte-derived macrophages (MDMs) than did ratios derived from uninduced cell lines. The altered Sp binding phenotype associated with changes in the transcriptional activation mediated by the HIV-1 G/C box array. Additionally, analysis of post-translational modifications on Sp1 and Sp3 revealed a loss of phosphorylation on serine and threonine residues with chemically-induced differentiation indicating that the activity of Sp factors is additionally regulated at the level of post-translational modifications (PTMs).

HIV-1 Vpr Functions in Primary CD4+ T Cells

“…About two decades ago, a study in Jurkat T cells postulated a correlation between Vpr’s abilities to transactivate the LTR and cause G2 arrest [ 53 ]. Since then, multiple other studies on this topic have been carried out on immortalized cell lines, including T cell-derived models, where it was observed that Vpr-dependent transactivation relies on its capacity to recruit various isoforms of the Sp transcription factor family to the LTR [ 54 , 55 , 56 ], although this effect proved highly cell type-dependent. Only in 2019 did the work of Hotter and collaborators finally demonstrate the importance of Sp1 availability towards viral expression in the context of CD4 + T cells, though the role of Vpr in this process was not assessed in their study [ 57 ].…”