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, but its role in HIV-1 infection has remained unclear. Here, we identify c-MET as a host factor that promotes HIV-1 replication in CD4 + T cells by facilitating viral entry. HIV-1 infection upregulates both c-MET transcript abundance and receptor phosphorylation in primary CD4 + T cells. Genetic knockout, knockdown, or pharmacological inhibition of c-MET in CD4 + T cells markedly reduced HIV-1 Gag protein expression, viral production, and infectivity. Integrative analyses using RNA sequencing, flow cytometry, and HIV-1 infection and entry assays revealed that c-MET disruption decreased cell-surface expression of the HIV-1 receptor CD4 and the coreceptor CXCR4, thereby limiting viral entry and subsequent infection. In addition, c-MET disruption attenuated activation of NF-κB, STAT1/3, and MAPK signaling pathways, which are critical regulators of HIV-1 gene expression. Together, these findings demonstrate that HIV-1 exploits HGF/c-MET signaling to coordinate entry receptor availability with intracellular signaling programs that support viral replication. Our study identifies a previously unrecognized host pathway required for efficient HIV-1 infection of primary CD4 + T cells and highlights HGF/c-MET signaling as a potential target for host-directed anti-HIV-1 therapeutic strategies. IMPORTANCE The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-MET) signaling pathway is a well-established regulator of cell growth, survival, and migration and has been extensively studied as a therapeutic target in cancer. However, its role in HIV-1 infection has remained unknown. In this study, we found that c-MET enhances HIV-1 infection of primary CD4 + T cells by facilitating viral entry. We further demonstrate that HIV-1 replication enhances HGF-dependent c-MET phosphorylation, which is required for downstream signaling. Genetic ablation or pharmacologic inhibition of c-MET reduces HIV-1 entry by decreasing expression of viral entry receptors. Moreover, c-MET inhibition or knockout disrupts activation of cellular signaling pathways, including NF-κB, JAK/STAT, and p38 MAPK. These findings reveal a previously unrecognized role for HGF/c-MET signaling in HIV-1 pathogenesis and suggest that targeting c-MET may represent a novel host-directed strategy for HIV-1 intervention.