Expression of the interleukin-18 gene from rhesus macaque by the simian immunodeficiency virus does not result in increased viral replication

Interleukin-18 (IL-18), previously known as interferon-γ (IFN-γ)-inducing factor (IGIF), is a proinflammatory cytokine expressed by activated macrophages that acts in synergy with IL-12 as an important amplifying factor for IFN-γ production and Th1 development. To study the effect of IL-18 on a lentiviral infection, we cloned the IL-18 gene from a rhesus macaque and constructed replication-competent simian immunodeficiency virus (SIV) that expressed either the precursor pro-IL-18 (SIV_IL-18) or the mature form (SIV_mIL-18) of IL-18. The predicted amino acid sequence for rhesus IL-18 had 96% homology with the human one, differing in only 8 of 193 residues. SIV_IL-18 and SIV_mIL-18 replicated more slowly than control viruses in the CEM × 3174 cell line and resulted in the development of chronically infected cell lines that expressed high levels of infectious SIV. The cell line generated by SIV_IL-18 released large quantities of IL-18 into the supernatant, whereas the one obtained from SIV_mIL-18 showed the accumulation of IL-18 in the cytoplasm. Similarly, SIV_IL-18 and SIV_mIL-18 replicated more slowly than the unmodified viral vector in rhesus peripheral blood mononuclear cells (PMBC), but only SIV_IL-18 expressed biologically active IL-18. These experiments show that the precursor form of IL-18 is necessary for the efficient release of the cytokine and that IL-18 does not promote increased replication of SIV in rhesus PBMC.