Therapy of ‘SHIV’ infected macaques with liposomes delivering antisense interleukin-4 DNA

Abstract

To explore the effects of antisense (AS) interleukin (IL)-4 on virus replication and CD8+ T-cell responses in lymph nodes and blood of macaques infected with simian human immunodeficiency virus, SHIV(89.6)P. Six macaques were inoculated with simian human immunodeficiency virus (SHIV(89.6)P). Seven days later, four of the animals were given 1 mg AS IL-4 plasmid complexed with Megafectin liposome, intravenously, and two of these received a second injection of the same material on day 9. All six macaques were killed at 2 weeks post infection (pi) and monitored for viral RNA and CD8+ T cells in blood and lymph nodes by real-time reverse transcriptase-polymerase chain reaction, flow cytometry and immunohistochemistry. In contrast to the lymph nodes from virus control animals, the lymph nodes of AS IL-4-treated animals had a significant reduction in viral loads and reduced depletion of cells from the nodes. There was an increase in CD8+ T cells in the nodes, and many of the cells expressed granzyme B, suggesting functional activation. This trend of virus reduction and increased CD8+ T cell numbers was also reflected in blood. The therapeutic effect of the AS IL-4 suggests indirectly that the acute immunosuppressive disease caused by SHIVs is mediated, in part, by IL-4 that causes enhanced virus replication by suppressing anti-viral CD8+ T-cell responses, and that this effect was reduced by treatment of the animals with AS IL-4.