title: Engagement of the CD4 receptor affects the redistribution of Lck to the immunological synapse in primary T cells: implications for T-cell activation during human immunodeficiency virus type 1 infection.
abstract: Understanding the molecular mechanisms underlying dysregulated immune responses in human immunodeficiency virus type 1 (HIV-1) infection is crucial for the control of HIV/AIDS. Despite the postulate that HIV envelope glycoprotein gp120-CD4 interactions lead to impaired T-cell responses, the precise mechanisms underlying such association are not clear. To address this, we analyzed Lck and F-actin redistribution into the immunological synapse in stimulated human primary CD4(+) T cells from HIV-1-infected donors. Similar experiments were performed with CD4(+) T cells from HIV-uninfected donors, which were exposed to anti-CD4 domain 1 antibodies, as an in vitro model of gp120-CD4 interactions, or aldithriol-inactivated HIV-1 virions before stimulation. CD4(+) T cells from HIV-infected patients exhibited a two- to threefold inhibition of both Lck and F-actin recruitment into the synapse, compared to cells from uninfected donors. Interestingly, defective recruitment of Lck was ameliorated following suppressive highly active antiretroviral therapy. Engagement of the CD4 receptor on T cells from HIV-uninfected donors before anti-CD3/CD28 stimulation led to similar defects. Furthermore, the redistribution of Lck into lipid rafts was abrogated by CD4 preengagement. Our results suggest that the engagement of CD4 by HIV gp120 prior to T-cell receptor stimulation leads to dysregulation of early signaling events and could consequently play an important role in impaired CD4(+) T-cell function.
authors.affiliation: Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA.
authors.forename: Alice M
authors.initials: AM
authors.lastname: Nyakeriga
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Fichtenbaum
authors.forename: Jens
authors.initials: J
authors.lastname: Goebel
authors.forename: Stella A
authors.initials: SA
authors.lastname: Nicolaou
authors.forename: Laura
authors.initials: L
authors.lastname: Conforti
authors.forename: Claire A
authors.initials: CA
authors.lastname: Chougnet
mesh_terms: D000199:Actins / Q000378:metabolism; D023241:Antiretroviral Therapy, Highly Active; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D054992:Immunological Synapses; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*
chemical_list: D000199:Actins; D015704:CD4 Antigens; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)