The HIV-1 Tat Protein Selectively Enhances CXCR4 and Inhibits CCR5 Expression in Megakaryocytic K562 Cells

Abstract

The hematopoietic compartments act as long-term reservoirs for human immunodeficiency virus type-1 (HIV-1). Although hematopoietic progenitor cells (HPCs) are rarely infectable, HPCs committed to the megakaryocytic lineage can be infected and support a productive infection by both the X4 and R5 strains of HIV-1. Indeed, in contrast to the CD34+ progenitors, the lineage-committed HPCs express high levels of the HIV-1 co-receptors, CXCR4 and CCR5. The HIV-1 transactivator (Tat) protein has been shown to alter co-receptor expression in T lymphocytes and macrophages. We hypothesized that Tat may regulate co-receptor expression in lineage-specific HPCs as well. We have monitored the effects of Tat protein on co-receptor expression and on lineage-specific differentiation, using the HPC cell line, K562. Butyric acid (BA)-induced erythroid differentiation in K562 cells was suppressed by 1-100 ng/ml of Tat, as evident from a 70-80% decrease in hemoglobin (Hb) production and a 10-30-fold decrease in glycophorin-A expression. However, Tat treatment enhanced phorbol myristate acetate (PMA)-induced megakaryocytic differentiation, as evident from a 180-210% increase in 3H-serotonin uptake and a 5-12-fold increase in CD61 expression. Tat did not significantly alter co-receptor expression in erythroid cells. However, Tat co-treatment profoundly effected both CXCR4 and CCR5 gene expression and protein levels in megakaryocytic cells. In PMA-stimulated cells, Tat increased CXCR4 and decreased in CCR5 expression, this was potentiated in cells chronically exposed to Tat. In conclusion, Tat protein suppresses erythroid and facilitates megakaryocytic differentiation of K562 cells. In megakaryocytic cells, Tat differentially effected CXCR4 and CCR5 expression. Because megakaryocytes may play a crucial role in HIV-1 infectivity in viral reservoirs, our findings implicate a role for Tat protein in dictating co-receptor usage in lineage-committed HPCs.

Immunomodulation by herpesvirus U51A chemokine receptor via CCL5 and FOG‐2 down‐regulation plus XCR1 and CCR7 mimicry in human leukocytes

“…The array included human chemokine receptor genes CCR1, CCR3, CCR5 and CXCR4. These receptors were not expressed in the K562 cells and there were no changes of expression in K562‐U51A cells consistent with previous reports on undifferentiated K562 cells 18. The chemokine genes included on the array were CXCR2 ligands CXCL8/IL8 or CXCL2/GROβ.…”

Infection of bone marrow cells by dengue virus in vivo

“…Altogether, data from these findings indicate that the DENV-antigen–positive cells belong to the megakaryocytic lineage as defined by the coexpression of CD41 and CD61. It has been documented previously that megakaryocytic cells, in addition to the expression of CD61 and CD41, also express the chemokine receptor CCR5, which becomes downregulated during the course of human immunodeficiency virus infection [27]. Therefore, it is possible that CCR5, which is the receptor for the chemokines macrophage inflammatory protein-1a, macrophage inflammatory protein-1b, and RANTES, may be an important molecule contributing to or preventing DENV disease in response to infection.…”

Mesenchymal stem cell derived hematopoietic cells are permissive to HIV-1 infection

“…Previous reports determined that the HIV-1 Tat protein alters co-receptor expression in lymphoid and myeloid cells [ 31 , 32 ]. Studies from our laboratory on the HPC cell line, K562 had also indicated that Tat can differentially regulate both CXCR4 and CCR5 expression in erythroid or megakaryocytic cells [ 33 ]. Although we have not measured Tat expression in the HD-HIV cells, the level of productive infection clearly suggests high levels of Tat protein which may be directly involved in changes in HIV-1 receptor expression observed in these cells.…”