Nef-mediated suppression of T cell activation was lost in a lentiviral lineage that gave rise to HIV-1.
High-level immune activation and T cell apoptosis represent a hallmark of HIV-1 infection that is absent from nonpathogenic SIV infections in natural primate hosts. The mechanisms causing these varying levels of immune activation are not understood. Here, we report that nef alleles from the great majority of primate lentiviruses, including HIV-2, downmodulate TCR-CD3 from infected T cells, thereby blocking their responsiveness to activation. In contrast, nef alleles from HIV-1 and a subset of closely related SIVs fail to downregulate TCR-CD3 and to inhibit cell death. Thus, Nef-mediated suppression of T cell activation is a fundamental property of primate lentiviruses that likely evolved to maintain viral persistence in the context of an intact host immune system. This function was lost during viral evolution in a lineage that gave rise to HIV-1 and may have predisposed the simian precursor of HIV-1 for greater pathogenicity in humans.
Schindler
Michael
M
Department of Virology, University of Ulm, 89081 Ulm, Germany.
Münch
Jan
J
Kutsch
Olaf
O
Li
Hui
H
Santiago
Mario L
ML
Bibollet-Ruche
Frederic
F
Müller-Trutwin
Michaela C
MC
Novembre
Francis J
FJ
Peeters
Martine
M
Courgnaud
Valerie
V
Bailes
Elizabeth
E
Roques
Pierre
P
Sodora
Donald L
DL
Silvestri
Guido
G
Sharp
Paul M
PM
Hahn
Beatrice H
BH
Kirchhoff
Frank
F
D000818:Animals; D017209:Apoptosis; D015704:CD4 Antigens / Q000276:immunology; D002478:Cells, Cultured; D016665:Cercocebus atys; D015536:Down-Regulation; D019143:Evolution, Molecular; D015693:Gene Products, nef / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*; D015498:HIV-2 / Q000276:immunology / Q000502:physiology; D006801:Humans; D017958:Lentiviruses, Primate / Q000276:immunology / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D010802:Phylogeny; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology; D015302:Simian Immunodeficiency Virus / Q000276:immunology / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D054311:nef Gene Products, Human Immunodeficiency Virus
D015704:CD4 Antigens; D015693:Gene Products, nef; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D054311:nef Gene Products, Human Immunodeficiency Virus