AEGiS-11IAC: HIV-1 infection abolishes CD4-dependent co-signalling via CD4/p56lCK disruption and induces apoptosis.

11th International AIDS Conference


Vancouver, British Columbia — July 7-12, 1996

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HIV-1 infection abolishes CD4-dependent co-signalling via CD4/p56lCK disruption and induces apoptosis.

Int Conf AIDS 1996 Jul 7-12; 11:225 (abstract no. Tu.A.380)
Guntermann C, Nye KE; Department of Immunology, St. Bartholomew's Hospital, London, UK. Fax: 0171 606 0845. E-mail: c.guntermann@mds.qmw.ac.uk.

OBJECTIVE: To investigate, in peripheral blood lymphocytes (PBLs), the effect of early HIV-1 infection on signal transduction events with respect to CD4 mediated co-stimulation of the CD3/T cell receptor (TcR) complex.

METHODS: PBLs were co-cultured with cell free isolates of HIV-1 (IIIb and RF) and with plasma from HIV-1 infected individuals (CDC group 4) for 10 days, stimulated with a combination of anti-CD3 and anti-CD4 antibodies and cell lysates were prepared. The tyrosine kinases p56lck and ZAP-70 were immunoprecipitated and subjected to kinase assays and western blot analysis. In conjunction, inositol polyphosphate profiles from stimulated PBLs were studied by high performance liquid chromatography. Apoptosis was measured using terminal deoxynucleotidyl transferase to label fragmented DNA with subsequent flow cytometric analysis. CD4 receptor expression was assessed by flow cytometry.

RESULTS: Tyrosine phosphorylation profiles induced by CD4 and CD3+CD4 ligation were profoundly abrogated in virally infected cells despite intact CD4 receptor expression (37% for infected and 35% for control PBLs). The interaction of the tyrosine kinase p56lck with the CD4 receptor was shown to be disrupted in HIV-infected cells which coincided with the inhibition of the activity of the down-stream tyrosine kinase ZAP-70 following activation by CD3+CD4 ligation. Phospholipase Cgamma mediated inositol phosphate generation following CD3+CD4 co-crosslinking was severely impaired in virally infected cells. This HIV-1 induced down-modulation of CD4 co-co-crosslinking was severely impaired in virally infected cells. This HIV-1 induced down-modulation of CD4 co-signalling of the TcR receptor pathway correlated directly with an increased incidence in apoptotic cell death.

CONCLUSIONS: Our results suggest abrogated CD4 co-stimulation via dissociation of p56lck from the CD4 receptor in HIV-1 infected cells. Failure to provide crucial co-signals by CD4 interfered with the integrity of TcR signalling. This was reflected by the lack of activation of ZAP-70, impaired generation of inositol phosphates and induction of apoptosis. Thus, these virally mediated perturbations in signalling during the course of HIV-1 infection might be relevant for HIV-1 pathogenesis, cell death and immunosuppression.

Keywords: AEGIS, Antigens, CD4, HIV Infections, HIV-1, Antigens, CD3, Apoptosis, Receptors, Antigen, T-Cell, Protein-Tyrosine Kinase, Signal Transduction, Phosphorylation, Tyrosine, ICA11KWDaegis,antigens,cd4,hivinfections,hiv-1,antigens,cd3,apoptosis,receptors,antigen,t-cell,protein-tyrosinekinase,signaltransduction,phosphorylation,tyrosine,ica11

960707
TuA380

Copyright © 1996 - International AIDS Society (IAS). Reproduction of this abstract (other than one copy for personal reference) must be cleared through the IAS.