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

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.