Nef

Nef is an accessory protein encoded by the nef gene of primate lentiviruses, most notably HIV-1, HIV-2, and related simian immunodeficiency viruses (SIV). In HIV-1, Nef is a small, ~23–25 kilodalton, cytoplasmic protein that is myristoylated at the second amino acid and associated with cellular membranes. Its name originates from early studies describing it as a “negative factor,” though Nef is now understood as a multifunctional regulator of host-cell biology.

Nef modulates the host cell environment in several ways that promote viral persistence and replication. It downregulates surface expression of CD4 and MHC class I molecules by routing these receptors to endosomal-lysosomal pathways, reducing susceptibility to immune detection and aiding virion release. Nef also perturbs T cell signaling by interacting with components of the T cell receptor pathway, which can enhance viral replication in activated T cells. Additionally, Nef influences the composition of the host cell membrane and endocytic machinery, in part through interactions with clathrin adaptor protein complexes AP-1 and AP-2, and by altering intracellular trafficking.

Structure and function are tightly linked, with the N-terminus bearing a myristoylation site necessary for membrane association and a flexible core region that engages various host factors. The protein is not an enzyme but acts as a regulatory adaptor that reshapes signaling and trafficking networks to favor viral propagation.

Clinical and research relevance centers on Nef’s contribution to pathogenicity in vivo; Nef-deficient viruses are typically attenuated in animal models, though Nef can be dispensable for replication in some cell culture systems. As such, Nef remains a focus of studies on HIV-1 pathogenesis and potential therapeutic strategies.