RECOMBINANT HUMAN IL-16 INHIBITS HIV-1 REPLICATION AND PROTECTS AGAINST ACTIVATION-INDUCED CELL-DEATH (AICD)

The chemoattractant cytokine IL-16 has been reported to suppress lymph ocyte activation and to inhibit HIV-1 replication in acutely infected T cells. We have cloned and expressed human IL-16 in Escherichia coli and investigated whether the recombinant protein could regulate the le vel of lymphocyte apoptosis from HIV-l-infected subjects. After purifi cation and refolding, only 2-10% of the recombinant cytokine was prese nt in a biologically active homotetrameric form. This could explain th e need for high concentrations of the bacterially derived IL-16 to ind uce significant inhibition of HIV-1 replication. Addition of IL-16 to unstimulated peripheral blood mononuclear cell (PBMC) cultures from HI V-l-infected subjects did not modify the observed level of spontaneous lymphocyte apoptosis. In contrast, IL-16 added to PBMC cultures stimu lated with anti-CD3, anti-CD95 or dexamethasone reduced significantly the percentage of lymphocytes undergoing AICD. This effect was found t o correlate with the ability of the cytokine to decrease CD95 expressi on on activated CD4(+) T cells. Comparative studies on PBMC from healt hy individuals indicated that the regulation of apoptosis levels by IL -16 is a complex phenomenon and could depend on the nature of the acti vator used and/or the immune status of lymphocytes tested. The outcome of CD4 cross-linking on T cells by various ligands is discussed in th e context of the observed beneficial activities of IL-16 and its poten tial role in the treatment of HIV disease.