HIV-1 Hijacks HGF/c-MET Signaling to Promote Viral Entry and Replication in Primary CD4⁺ T Cells

Abstract

The mesenchymal-epithelial transition factor (c-MET) is a receptor tyrosine kinase best known for mediating hepatocyte growth factor (HGF) signaling in cancer, yet its role in HIV-1 infection remains undefined. Here we identify c-MET as a host factor that facilitates HIV-1 replication in CD4+ T cells by promoting viral entry. HIV-1 infection upregulates c-MET transcripts and phosphorylation in primary CD4+ T cells. Knockout or pharmacological inhibition of c-MET in CD4+ T cells significantly reduces HIV-1 Gag expression, viral production, and infectivity. Mechanistically, c-MET disruption reduces cell-surface expression of the HIV-1 receptor CD4 and the coreceptor CXCR4, thereby restricting viral entry and infection. Furthermore, c-MET disruption diminishes activation of NF-{kappa}B, STAT1/3, and MAPK signaling pathways that are critical for HIV-1 gene expression. These findings reveal that HIV-1 exploits HGF/c-MET signaling to coordinate entry receptor availability and intracellular signaling, uncovering a previously unrecognized host pathway that supports viral replication in CD4+ T cells. Overall, our results highlight an essential role for HGF/c-MET signaling in HIV-1 infection of primary CD4+ T cells and suggest a potential host-directed therapeutic target. HighlightsO_LIc-MET facilitates HIV-1 replication in CD4+ T cells by promoting viral entry C_LIO_LIHIV-1 infection upregulates c-MET transcripts and phosphorylation in CD4+ T cells C_LIO_LIc-MET disruption reduces CD4 and CXCR4 expression on CD4+ T cell surfaces C_LIO_LIc-MET disruption diminishes activation of cellular pathways important for HIV-1 C_LI