Human immunodeficiency virus type 1 Negative regulatory factor (HIV-1 Nef) (Nef)

Human immunodeficiency virus type 1 Negative regulatory factor (HIV-1 Nef) is a critical accessory protein required for viral pathogenesis and the progression to AIDS. Although it lacks intrinsic enzymatic activity, Nef functions as a potent molecular adaptor that hijacks host cell protein trafficking and signal transduction pathways. Its primary biological roles include the downregulation of surface CD4 receptors to prevent viral superinfection and the internal sequestration of MHC-I molecules to shield infected cells from cytotoxic T-lymphocyte-mediated destruction (UniProt P03406). Nef also enhances viral infectivity and promotes T-cell activation, which facilitates viral replication and the maintenance of the viral reservoir. Because individuals infected with Nef-deleted HIV-1 strains typically exhibit low viral loads and do not progress to AIDS, Nef is considered a high-value therapeutic target for immune restoration (PubMed: 22457320). Current drug discovery efforts focus on small molecules and PROTACs that disrupt Nef's interaction with host SH3-domain-containing proteins, such as Hck and other Src-family kinases, to restore immune recognition of infected cells (PubMed: 30305450). While no Nef-specific inhibitors are currently FDA-approved, repurposed kinase inhibitors like Dasatinib have shown the ability to block certain Nef-dependent signaling pathways in experimental models (PubMed: 25713392).

Other names

Negative regulatory factor3'ORFF-proteinp27Nef protein

Inhibition of Nef-mediated host cell signaling hijacking and disruption of Nef-host protein-protein interactions, particularly with Src-family kinases.