HIV-Nef and AIDS pathogenesis: are we barking up the wrong tree?

After two decades of research the Nef protein of human immunodeficiency virus (HIV) remains a mysterious protein with an indisputable role in HIV pathogenesis. The ability to downregulate CD4 and major histocompatibility complex class I (MHC-I) was the first ascribed function of Nef and, whereas the number of downmodulated receptors by Nef is rising, so are the explanations for how their downregulation could contribute to HIV pathogenesis. At the same time there is increasing evidence that Nef not only induces endocytosis but also exocytosis, namely of cytokines and microvesicles that contain Nef itself. Because endocytosis and exocytosis are connected events, this is not surprising - and raises the intriguing possibility that HIV aims at secretion rather than ingestion. Have we therefore barked up the wrong tree over the past two decades? In this opinion article I argue that Nef-induced secretion is most probably the pathogenesis-relevant function behind this elusive viral effector.