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

A recent study has uncovered an unexpected role for the HGF/c-MET signaling pathway in the replication of HIV-1 within primary CD4+ T cells. The mesenchymal-epithelial transition factor (c-MET) is typically associated with regulating hepatocyte growth factor (HGF) signaling in cancer, but its involvement in HIV-1 infection had not been previously identified.

The researchers found that HIV-1 infection leads to an increase in c-MET transcripts and phosphorylation in primary CD4+ T cells. When c-MET was knocked out or inhibited pharmacologically in these cells, HIV-1 replication was significantly reduced, as evidenced by decreased levels of the viral protein Gag, lower viral production, and diminished infectivity.

By disrupting c-MET, the researchers observed a reduction in the expression of both CD4 and CXCR4, the coreceptors necessary for HIV-1 entry into CD4+ T cells. This suggested that c-MET plays a crucial role in maintaining these receptor availability, thereby facilitating viral entry.

Furthermore, the study revealed that c-MET inhibition dampened the activation of key signaling pathways such as NF-{kappa}B, STAT1/3, and MAPK, which are essential for the expression of HIV-1 genes. This indicates that c-MET signaling not only modulates receptor availability but also influences the intracellular signaling necessary for viral gene expression.

These findings demonstrate that HIV-1 exploits the HGF/c-MET signaling pathway to orchestrate both the availability of viral entry receptors and the intracellular pathways required for viral replication in primary CD4+ T cells. The discovery highlights an essential role for HGF/c-MET signaling in HIV-1 infection of these cells and suggests that targeting this host factor could be a promising therapeutic strategy to combat HIV-1 infection.