The Presence of a vpu Gene and the Lack of Nef-Mediated Downmodulation of T Cell Receptor-CD3 Are Not Always Linked in Primate Lentiviruses
Creators: name: Schmökel, Jan
name: Sauter, Daniel
name: Schindler, Michael
name: Leendertz, Fabian
name: Bailes, Elizabeth
name: Dazza, Marie-Christine
name: Saragosti, Sentob
name: Bibollet-Ruche, Frederic
name: Peeters, Martine
name: Hahn, Beatrice H.
name: Kirchhoff, Frank
Publisher: name: Robert Koch-Institut
Year: 2010
Subjects: subject: Animals
subject: Antigens
subject: Simian immunodeficiency virus/genetics
subject: Simian immunodeficiency virus/immunology
subject: Receptors
subject: Primates
subject: Simian Acquired Immunodeficiency Syndrome/virology
subject: Simian immunodeficiency virus/isolation &amp; purification
subject: Down-Regulation
subject: CD/biosynthesis
subject: Genes vpu
subject: Antigen
subject: T-Cell/antagonists &amp; inhibitors
subject: Simian Acquired Immunodeficiency Syndrome/immunology
subject: Viral Regulatory and Accessory Proteins/immunology
subject: 610 Medizin

description: Nef is an accessory protein critical for the ability of human and simian immunodeficiency viruses (HIV and SIV) to replicate efficiently in their respective hosts. Previous analyses of members of 15 different primate lentivirus lineages revealed a link between Nef function and the presence of a vpu gene. In particular, Nef proteins of all vpu-containing viruses had lost their ability to downmodulate the T cell (TCR-CD3) receptor. Here we examined Nef proteins from eight additional SIV lineages, including SIVgor, SIVwrc, SIVolc, SIVgri, SIVdrl, SIVlho, SIVden, and SIVasc, from western lowland gorillas, western red colobus monkeys, olive colobus monkeys, grivet monkeys, drills, L'Hoest's monkeys, Dent's mona monkeys, and red-tailed monkeys, respectively. We found that except for the nef gene of SIVdrl, all of them were efficiently expressed and modulated CD4, major histocompatibility complex class I (MHC-I), CD28, CXCR4, and Ii cell surface expression and/or enhanced viral infectivity and replication. Furthermore, the Nef proteins of SIVgri, SIVlho, SIVwrc, SIVolc, and SIVgor antagonized tetherin. As expected, the Nef protein of SIVgor, which carries vpu, failed to downmodulate CD3, whereas those of SIVwrc, SIVgri, SIVlho, and SIVasc, which lack vpu, were capable of performing this function. Surprisingly, however, the Nef protein of the vpu-containing SIVden strain retained the ability to downmodulate TCR-CD3, whereas that of SIVolc, which does not contain vpu, was unable to perform this function. Although the SIVden Vpu is about 20 amino acids shorter than other Vpu proteins, it degrades CD4 and antagonizes tetherin. Our data show that there are exceptions to the link between the presence of a vpu gene and nef alleles deficient in CD3 modulation, indicating that host properties also affect the selective pressure for Nef-mediated disruption of TCR-CD3 signaling. Our results are also further evidence that tetherin antagonism is a common function of primate lentivirus Nef proteins and that the resistance of human tetherin to Nef represents a relevant barrier to cross-species transmission of SIVs to humans.