Functional Fas-ligand expression on T cells from HIV-1-infected patients is unrelated to CD4+ lymphopenia

• DOI: 10.1007/s005990050048
• Publication Date: 2003-12-02T23:33:36Z
• Authors: F. Silvestris; P. Cafforio; G. Camarda; M. Tucci; M. A. Frassanito; F. Dammacco
• Keywords: CD4-Positive T-Lymphocytes; Fas Ligand Protein; Membrane Glycoproteins; Gene Expression; Apoptosis; HIV Infections; Flow Cytometry; Polymerase Chain Reaction; Immunophenotyping; 3. Good health; Interferon-gamma; 03 medical and health sciences; 0302 clinical medicine; Lymphopenia; HIV-1; Linear Models; Humans; RNA, Messenger; fas Receptor; Biomarkers; DNA Primers

Recent studies have demonstrated that the expression of Fas by peripheral T cells from HIV-1+ patients is deregulated and increases the susceptibility of these cells to undergo apoptosis. Here, we show that secretion of Fas-ligand (L), the complementary agonist of Fas, is abnormally upregulated in CD4+ cells from HIV-1-infected individuals, particularly during the non-lymphopenic stages of the disease. An increase of soluble Fas-L occurred in T cell cultures from 26 patients with a number of CD4+ cells higher than 400/microliter, whereas it was almost undetectable in cultures from 21 severely lymphopenic patients (CD4+ < 200/microliter). The MTT test, cytofluorimetric analysis of cellular DNA, cytotoxicity, and proliferative assays using the Fas-transfected WC8 mouse lymphoma confirmed the cytocidal capability of T cell supernatants from non-lymphopenic patients. Double-fluorescence analysis revealed that the majority of CD4+ cells (approximately 90%) in these cultures secreted Fas-L in the presence of high intracellular gamma-interferon and low Bcl-2. In contrast, the CD8+/Fas-L+ population was comparably decreased (approximately 55%). Molecular cloning of Fas-L revealed a substantial expression of Fas-L mRNA in cells from non-lymphopenic patients compared with patients with advanced disease and healthy controls. Since CD4+ cells of Th1 phenotype are impaired during HIV-1 infection and show high cellular expression of Fas-L, it is conceivable that excess Fas-L during the early or non-lymphopenic phase of the disease increases the extent of apoptosis in these cells by the Fas/Fas-L pathway. The defective expression of the ligand in severely lymphopenic stages could be explained by exhaustion of this mechanism as the disease progresses.