oa Editorial [Nef: A Notorious Enigmatic Factor in HIV Biology (Guest Editor: Bruno Verhasselt)]

Ever since the protein received its inappropriate acronym “negative facor”, the primate lentiviral Nef protein has opened a field of research marked by controversy. Two decades after the discovery of its importance for pathogenic infection of rhesus macaques followed by similar observations in HIV infected humans, the mechanism of action of this protein remains notoriously enigmatic, a puzzle that is solved only piece by piece. Nef is thought to be exclusively involved in virus-host interactions. It has no catalytical nor structural function, but serves as an adaptor protein. It significantly enhances virus infection and spread in primary T cells or in ex vivo infected lymphoid tissues. It affects T cell activation, T cell development and trafficking of several cellular proteins like CD4, CD8, CD28, CXCR4, CCR5, MHC class I and II. The identification of new cellular interaction partners and the understanding of the interaction of Nef with these and already known partners will not only increase our basic understanding of HIV replication but will also provide new therapeutic avenues to interfere with HIV replication. In this themed issue, several research groups active in Nef research review our current knowledge. The enhancement of primate lentivirus infectivity by Nef is reviewed by Vermeire et al. They discuss the mechanisms proposed to explain this property of the protein, affecting the virion composition and the early events post-infection of the target cell. Margherita Doria reviews the controversy on the importance of CD4 downregulation by Nef in both the producer and target cell for enhanced virion infectivity by Nef. The downregulation of cell surface molecules like CD4 by Nef and the possible advantageous consequences for viral infection, replication, and evasion from immunity is the focus of the review by Landi et al. While most knowledge on Nef is gathered from the study of the protein in lymphocytes and derived cell lines, it is clear that expression of the protein affects both the viral life cycle as well as cellular functions in macrophages, as reviewed by Yanina Ghiglione and Gabriela Turk. The challenges primate lentiviruses have overcome during inter-species transmission reveal the plasticity of the viral proteins, needed to interact with different species-specific host protein domains. The impairment of the tetherin restriction factor function by Nef illustrates this plasticity, reviewed by Daniel Sauter and Frank Kirchhoff. Despite species differences, the expression of Nef driven by the regulatory sequences of the human CD4 gene in transgenic mice causes disease, reminiscent to AIDS in humans. Paul Jolicoeur reviews what this model can learn us on the contribution of Nef to morbidity of HIV infection. In the search for the molecular mechanism behind the Nef functions reviewed in this issue, most progress was made in the study of the interaction of Nef with Src homology-3 (SH3) domains of cellular host proteins. The biological and therapeutic relevance of this interaction is reviewed by Kalle Saksela. As the molecular details of this and other Nef - host protein interaction are being unveiled, targeted therapies can be developed. Lulf et al. discuss recent progress in this field. While the enigma has not been solved, a lot progress has been made in our understanding of the function of lentiviral Nef. By these revelations, both the beauty of the viruses as a possible Achilles' heel to target therapeutically are exposed.