Lymphocyte activation in HIV-1 infection. I. Predominant proliferative defects among CD45RO+ cells of the CD4 and CD8 lineages


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Abstract

Objectives and designThe proliferative defects of CD4 and CD8 cells taken from 474 HIV-1-seropositive individuals during various stages of disease were quantitated. Phytohaemagglutinin (PHA) and soluble anti-CD3 were used in optimal mitogenic concentrations in the presence of recombinant interleukin-2 (rlL-2) and conditioned medium, and the proliferation of cells from HIV-1-seropositive donors was assessed in co-culture with HIV-1-seronegative cells in order to exclude effects of cytokine deficiency. Defects within the CD45RA+ ('unprimed') and CD45RO+ ('primed') T-cell populations were also investigated.MethodsQuantitative immunofluorescence and double and triple labelling in flow cytometry were performed for (1) CD25 (IL-2 receptor a chain) expression, (2) lymphocyte and T-cell survival, and (3) blast transformation and proliferation — in relation to the original input of cells for each subpopulation.ResultsT cells from normal and HIV-1-seropositive donors were CD25+ at day 1. In HIV-1-seropositive patients a variable number of CD4 and CD8 lymphocytes failed to further increase CD25, and died as a sign of activation-associated lymphocyte death (AALD). Forty-two per cent of asymptomatic subjects, including 32% of those with CD4 cell counts > 400 χ 106/1, showed a poor blast transformation (< 30% blasts). Cells from HIV-1-seropositive donors showed poor blast responses when co-cultured with HIV-1-seronegative cells; both CD4 and CD8 cells were handicapped. In asymptomatic HIV-1-seropositive people T cells with the CD45RO+ RA- ('primed') phenotype were three to five times more vulnerable to AALD than the CD45RA+ RO—('unprimed') cells. In patients in Centers for Disease Control and Prevention (CDC) disease stage IV both CD45RO+ and -RA+ populations were severely affected.ConclusionsThis is the first quantitative analysis to demonstrate that in HIV-1 infection mitogen-stimulated CD45RO+ ('primed') T cells preferentially die upon activation. Both the CD4 and CD8 lineages are affected, as seen in animal models of graft versus host disease. AALD may explain defects of immunological memory. The analysis of AALD may be a suitable assay for studying whether antiviral drugs influence the proliferative responses of lymphocytes.

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