1. Academic Validation
  2. JAK/STAT signaling pathway affects CCR5 expression in human CD4+ T cells

JAK/STAT signaling pathway affects CCR5 expression in human CD4+ T cells

  • Sci Adv. 2024 Mar 22;10(12):eadl0368. doi: 10.1126/sciadv.adl0368.
Lingyun Wang 1 Yunus Yukselten 1 Julius Nuwagaba 1 Richard E Sutton 1
Affiliations

Affiliation

  • 1 Section of Infectious Diseases, Department of Internal Medicine, Yale University, New Haven, CT, USA.
Abstract

CCR5 serves as R5-tropic HIV co-receptor. Knocking out CCR5 in HIV patients, which has occurred <10 times, is believed important for cure. JAK/STAT inhibitors tofacitinib and ruxolitinib inhibit CCR5 expression in HIV+ viremic patients. We investigated the association of JAK/STAT signaling pathway with CCR5/CCR2 expression in human primary CD4+ T cells and confirmed its importance. Six of nine JAK/STAT inhibitors that reduced CCR5/CCR2 expression were identified. Inhibitor-treated CD4+ T cells were relatively resistant, specifically to R5-tropic HIV Infection. Furthermore, single JAK2, STAT3, STAT5A, and STAT5B knockout and different combinations of JAK/STAT knockout significantly reduced CCR2/CCR5 expression of both RNA and protein levels, indicating that CCR5/CCR2 expression was positively regulated by JAK-STAT pathway in CD4+ T cells. Serum and glucocorticoid-regulated kinase 1 (SGK1) knockout affected CCR2/CCR5 gene expression, suggesting that SGK1 is involved in CCR2/CCR5 regulation. If cell surface CCR5 levels can be specifically and markedly down-regulated without adverse effects, that may have a major impact on the HIV cure agenda.

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