HIV-1 negative regulatory factor (HIV-1 Nef)

HIV-1 Nef is a small myristoylated accessory protein (27–35 kDa) encoded by the HIV-1 genome and expressed early in the viral life cycle[1][5]. Despite its name (“Negative regulatory factor”), it strongly *promotes* viral replication, pathogenesis, and immune escape. Nef is a non-enzymatic protein that functions primarily through dynamic protein–protein interactions, especially with host cell signaling and trafficking proteins, including Src-family kinases (via a conserved SH3-binding proline-rich motif)[1][3][5][6][7]. Nef mediates several critical functions in the HIV-infected cell: downregulation of CD4 and MHC class I from the cell surface, altered T-cell receptor signaling, cytoskeletal rearrangement, and enhancement of virion infectivity. Nef is indispensable for disease progression in vivo: deletion or mutation of *nef* reduces viral pathogenicity, delays progression to AIDS, and impairs viral replication in animal models and humans[1][2]. Due to these key roles, Nef is recognized as a major virulence and therapeutic target, though no approved drugs currently act directly on Nef[1][6].

Other names

NefNegative regulatory factorNegative factorF-protein

Experimental inhibitors generally aim to:\n- Block Nef-host SH3 domain interactions (disruption of protein-protein interactions)[6][7]\n- Inhibit Nef myristoylation, thereby preventing membrane localization[1]\n- Restore cell surface levels of CD4 and MHC I to improve immune detection of infected cells[1][7]