Role of interleukin-8 and transforming growth factor-beta 1 in enhancementof human cytomegalovirus replication by human T cell leukemia-lymphoma virus type I in macrophages coinfected with both viruses

Human cytomegalovirus (HCMV) is one of the most frequent opportunistic agen ts causing severe illness in chronic human T cell leukemia-lymphoma virus t ype I (HTLV-T) infection. Our previous studies have shown that coinfection of macrophages with HCMV and HTLV-I significantly enhances HCMV replication , resulting in release of infectious HCMV from dually infected cells. We fo und that double infection of macrophages with HCMV and HTLV-I induced a rap id production of substantial amounts of interleukin-8 (IL-8) and transformi ng growth factor-beta 1 (TGF-beta 1). Results of transfection studies demon strated that the tax gene product of HTLV-I was able to induce secretion of IL-8 and TGF-beta 1. In addition to its cytokine-inducing effect, the Tax protein could interact with HCMV synergistically to result in production of much higher levels of IL-8 and TGF-beta 1 than expected on the basis of th eir separate activities. Treatment of dually infected macrophage cultures w ith neutralizing antibodies to IL-8 and TGF-beta 1 led to a nearly 1000-fol d decrease in release of infectious HCMV from coinfected cells, Similar res ults were obtained when anti-IL-8 and anti-TGF-beta 1 treatments were combi ned in macrophage cultures transfected with the tax gene before HCM IV infe ction. Our results suggest that the stimulatory effect of HTLV-I Tax protei n on HCMV replication in coinfected macrophages is largely mediated by high levels of IL-8 and TGF-beta 1 production.