title: T-cell receptor:CD3 down-regulation is a selected in vivo function of simian immunodeficiency virus Nef but is not sufficient for effective viral replication in rhesus macaques.
abstract: We investigated the function of severely truncated simian immunodeficiency virus (SIV) Nef proteins (tNef) in vitro and in vivo. These variants emerged in rhesus monkeys infected with SIVmac239 containing a 152-bp deletion in the nef-unique region and have been suggested to enhance SIV virulence (E. T. Sawai, M. S. Hamza, M. Ye, K. E. Shaw, and P. A. Luciw, J. Virol. 74:2038-2045, 2000). We found that the tNef proteins were unable to down-regulate the cell surface expression of major histocompatibility complex class I proteins, CD4, and CD28 and neither stimulated SIV replication nor enhanced virion infectivity. The tNef proteins did efficiently down-regulate T-cell receptor (TCR):CD3 cell surface expression. Nevertheless, the SIVmac239 tnef variants were strongly attenuated in six infected juvenile rhesus macaques. Thus, while the ability of SIV Nef to down-modulate TCR:CD3 cell surface expression apparently confers a selective advantage in vivo, it is insufficient for efficient viral replication in infected macaques. Additional mutations elsewhere in SIVmac239 tnef genomes are required for a virulent phenotype.
authors.affiliation: Abteilung Virologie, Universitätsklinikum, 89081 Ulm, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Münch
authors.forename: Ajit
authors.initials: A
authors.lastname: Janardhan
authors.forename: Nicole
authors.initials: N
authors.lastname: Stolte
authors.forename: Christiane
authors.initials: C
authors.lastname: Stahl-Hennig
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Haaft
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Heeney
authors.forename: Tomek
authors.initials: T
authors.lastname: Swigut
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
authors.forename: Jacek
authors.initials: J
authors.lastname: Skowronski
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015536:Down-Regulation; D015754:Genes, nef; D014644:Genetic Variation; D006801:Humans; D019169:Jurkat Cells; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics* / Q000276:immunology / Q000502:physiology*; D014774:Virulence / Q000235:genetics; D014779:Virus Replication / Q000235:genetics / Q000276:immunology / Q000502:physiology*
chemical_list: C429284:NEF protein, SIV; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D054334:Viral Regulatory and Accessory Proteins