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

Lingyun Wang1, Yunus Yukselten1, Julius Nuwagaba1

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

Science Advances
|March 20, 2024
PubMed

Insights

Targeting the JAK/STAT pathway with inhibitors can reduce CCR5 and CCR2 expression on CD4+ T cells. This finding is crucial for developing new strategies against R5-tropic HIV infection and advancing HIV cure research.

Area of Science:

  • Immunology
  • Virology
  • Molecular Biology

Background:

  • CCR5 is a key co-receptor for R5-tropic HIV entry into CD4+ T cells.
  • CCR5 downregulation is a potential strategy for HIV cure, but achieving this safely and effectively remains a challenge.
  • The JAK/STAT signaling pathway is implicated in various cellular processes, including immune cell function.

Purpose of the Study:

  • To investigate the association between the JAK/STAT signaling pathway and the expression of CCR5 and CCR2 in human primary CD4+ T cells.
  • To identify JAK/STAT inhibitors that can effectively reduce CCR5/CCR2 expression.
  • To assess the impact of modulating this pathway on HIV resistance.

Main Methods:

  • Treatment of primary CD4+ T cells with JAK/STAT inhibitors (e.g., tofacitinib, ruxolitinib).
  • Genetic manipulation using single and combined knockouts of JAK/STAT pathway components (JAK2, STAT3, STAT5A, STAT5B).
  • Analysis of CCR5/CCR2 expression at both RNA and protein levels, and assessment of cellular resistance to R5-tropic HIV infection.

Main Results:

  • Six of nine tested JAK/STAT inhibitors significantly reduced CCR5/CCR2 expression in CD4+ T cells.
  • Inhibitor-treated cells exhibited increased resistance to R5-tropic HIV infection.
  • Knockout of JAK2, STAT3, STAT5A, and STAT5B individually or in combination markedly decreased CCR5/CCR2 expression, confirming positive regulation by the JAK-STAT pathway.
  • Serum and glucocorticoid-regulated kinase 1 (SGK1) knockout also affected CCR2/CCR5 gene expression, suggesting its involvement.

Conclusions:

  • The JAK-STAT signaling pathway positively regulates CCR5 and CCR2 expression in CD4+ T cells.
  • Targeting this pathway with specific inhibitors offers a promising strategy for reducing HIV co-receptor expression.
  • Further research into specific JAK/STAT inhibitors and SGK1 could lead to novel therapeutic approaches for HIV cure.

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