title: HIV-1 Nef disrupts maturation of CD4+ T cells through CD4/Lck modulation.
abstract: The HIV-1 Nef protein is a major determinant of HIV-1 pathogenicity. It has been found to induce thymocyte depletion, but the mechanisms involved are not completely understood. Also, nothing is known about its effects on thymocyte selection. We used the CD4C/HIV(Nef) transgenic (Tg) mice, which develop a profound CD4(+) T cell lymphopenia, to study their thymic development. We report that HIV-1 Nef causes depletion of double-positive thymocytes and impairs selection and lineage commitment of CD4(+) single-positive thymocytes. This latter defect could be relieved by increasing the affinity of the TCR-MHC interaction or by allowing CD4(+) T cell maturation to proceed in absence of the CD4 tail, in double-Tg (Nef × CD4(tailless)) mice or in the presence of constitutively active Tg Lck(Y505F). These rescue strategies also resulted in reversal of peripheral CD4(+) T cell lymphopenia. Our data indicate that impairment of Lck-mediated CD4 coreceptor signaling by Nef is an important in vivo mechanism of HIV-1 pathogenesis.
authors.affiliation: Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada. pavel.chrobak@ircm.qc.ca
authors.forename: Pavel
authors.initials: P
authors.lastname: Chrobak
authors.forename: Marie-Chantal
authors.initials: MC
authors.lastname: Simard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bouchard
authors.forename: Thomas Mutushi
authors.initials: TM
authors.lastname: Ndolo
authors.forename: Joël
authors.initials: J
authors.lastname: Guertin
authors.forename: Zaher
authors.initials: Z
authors.lastname: Hanna
authors.forename: Vibhuti
authors.initials: V
authors.lastname: Dave
authors.forename: Paul
authors.initials: P
authors.lastname: Jolicoeur
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000821:virology*; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D015151:Immunoblotting; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology* / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D054311:nef Gene Products, Human Immunodeficiency Virus; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)