Nef is an accessory protein expressed exclusively in primate lentiviruses. It is devoid of enzymatic
activities while interacting with several cell proteins as an adaptor/scaffold protein. Intracellular
functions of Nef largely account for many pathogenic effects observed in AIDS disease. Nef, despite
lacking known secretory pathways, can be detected in plasma of HIV-1-infected patients at the
concentration varing from 5 to 10 ng/ml. Remarkably, the levels of Nef in plasma of HIV patients do
not correlate with viral load or number of CD4+ T lymphocytes, and persist during antiretroviral therapy.
Here, we review literature data describing how Nef can be transmitted from HIV-1- infected cells
to bystander ones, and the effects of extracellular Nef in different cell types. Overall, large part of experimental
evidences supports the idea that extracellular Nef plays a relevant role in AIDS pathogenesis. Hence, efforts
focused on the identification of Nef-inhibiting drugs would be of relevance to establish new therapeutic approaches supporting
current antiretroviral therapies.