Programmed death of both CD4+ and CD8+ cells in asymptomatic HIV-infection.
Int Conf AIDS 1992 Jul 19-24; 8:We53 (abstract no. WeA 1045) Meyaard L, Otto SA, Jonker RR, Mijnster MJ, Keet IP, Miedema F; Centr Lab of the Neth Red Cross Blood Transf Service, Amsterdam.
OBJECTIVES. The early stage of human immunodeficiency virus (HIV) infection is characterized by qualitative functional defects of antigen-reactive T cells. With only few cells infected, this can not be explained by direct viral infection. We hypothesized that probably due to a systemic immune dysregulation, T-cells from HIV-infected individuals reach an anergic or hyperactivated state which primes them for programmed cell death (PCD) upon antigenic stimulation. METHODS. Freshly isolated PBMC from asymptomatic HIV-infected individuals were analyzed for death due to PCD by electron microscopy, DNA fragmentation assay and by quantitating cells engaged in PCD, specifically labelled by incorporating biotin-labelled nucleotides into the DNA of cells with DNA-strand breaks. RESULTS. After overnight culture, T cells from asymptomatic HIV-infected individuals (n = 29) showed condensed chromatin morphology and DNA-fragmentation characteristic for PCD. DNA fragmentation could be prevented by the addition of Zn2+, known to inhibit endonuclease activity in PCD. Cell death was observed in both CD4+ and CD8+ T-cells. In HIV-infected individuals (n = 34) the percentage of cells dying due to PCD was +/- 15% and could be increased by polyclonal stimulation via the CD3/T-cell receptor complex up to +/- 25%. CONCLUSIONS. PCD, associated with impaired T-cell reactivity in vitro, offers a systemic explanation for deletion of reactive T cells which may contribute to HIV-induced immunodeficiency in vivo. Gradual deletion of immune regulatory T cells by PCD may contribute to attenuation of the immune system, which will eventually allow high-rate viral replication and emergence of highly cytopathic HIV variants associated with accelerated loss of CD4+ cells, and rapid progression to AIDS.
Keywords: AEGIS, Antigens, CD8, Antigens, CD4, HIV Infections, HIV, Acquired Immunodeficiency Syndrome, T-Lymphocytes, Antigens, CD3, Receptors, Antigen, T-Cell, Apoptosis, Simian Acquired Immunodeficiency Syndrome, HIV Envelope Protein gp120, Cell Death, Anti-HIV Agents, Virus Replication, Human, In Vitro, virology, ICA8
920719
WeA1045
