Human immunodeficiency virus type 1 Negative Factor (HIV-1 Nef) (HIV-1 Nef)

Human immunodeficiency virus type 1 Negative Factor (HIV-1 Nef) is a 27-35 kDa myristoylated accessory protein essential for high-titer viral replication and the progression of HIV infection to AIDS. Nef lacks intrinsic enzymatic activity and instead functions as a versatile adaptor protein, hijacking host cell signaling and trafficking machinery through various protein-protein interaction motifs. A critical aspect of Nef's function is its ability to form homodimers; the homodimer interface is essential for several of its pathogenic activities, including the downregulation of MHC-I from the surface of infected cells, which allows the virus to evade cytotoxic T-lymphocyte recognition. Targeting the HIV-1 Nef homodimer interface represents a promising therapeutic strategy because Nef has no human homologs, potentially reducing the risk of host toxicity. Small molecule inhibitors designed to disrupt this interface or stabilize an inactive conformation have demonstrated the ability to restore MHC-I expression and inhibit Nef-dependent activation of host kinases like Hck. While no Nef inhibitors are currently approved for clinical use, research into the structural biology of the Nef dimer interface continues to provide a foundation for developing novel antiretroviral therapies that complement existing protease and reverse transcriptase inhibitors.

Other names

NefNegative Factor3'ORFHIV-1 Nef homodimer interface

Inhibition of Nef homodimerization or disruption of the homodimer interface to prevent Nef-mediated downregulation of host cell surface receptors and inhibit viral pathogenesis.