Nef (Negative Regulatory Factor) is a small 27-35 kDa myristoylated protein encoded by primate lentiviruses.

Nef localizes primarily to the cytoplasm but also partially to the Plasma membrane (PM) and is one of many pathogen-expressed proteins, known as virulence factors, which function to manipulate the host's cellular machinery and thus allow infection, survival or replication of the pathogen.

Nef retargets kinase-active Lck away from the plasma membrane to early and recycling endosomes (RE) as well as the Trans-Golgi network (TGN).

Lentiviruses such as HIV-1 have acquired proteins such as Nef which perform a wide array of functions including the identification of CTLA-4 before it reaches the PM and tagging it for degradation.

[citation needed] Cytoskeletal remodeling is thought to reduce TCR signaling during early infection and is also modulated to some degree by Nef.