Pentoxifylline Promotes Replication of Human Cytomegalovirus In Vivo and In Vitro

Abstract

AbstractOKT3 monoclonal antibody (MoAb) therapy is well established in the prevention and therapy of acute rejection in transplant patients. Unfortunately, this therapy is associated with several short-term (cytokine release syndrome) and long-term (infections, EBV-related lymphoma) side effects. Recently, we were able to demonstrate an association between the TNFα release following the first OKT3 MoAb infusions and the appearance of human cytomegalovirus (HCMV) reactivation several days later. In order to prevent this TNFα associated HCMV reactivation patients were additionally treated with pentoxifylline (PTX), a methylxanthine derivative that has been shown to suppress TNFα induction. Although the TNFα peak plasma level following OKT3 MoAb treatment was markedly reduced, the incidence of HCMV reactivation and HCMV disease was not influenced. In transient transfection experiments using HCMV immediate early enhancer/promoter CAT reporter gene constructs PTX enhanced the promoter activity independently from TNFα in premonocytic cells. Furthermore, PTX acted synergistically with TNFα. In virus-infected human embryonal lung fibroblasts HCMV replication was triggered in the presence of both PTX and TNFα, while either substance alone had only marginal effects. The stimulatory effect of PTX on the immediate early (IE) enhancer/promoter was mediated via CREB/ATF, a eukaryotic transcription factor that binds to the 19 bp sequence motif in the enhancer region, while TNFα stimulation was mediated by activation of the transcription factor NF-kB and its binding to the 18 bp sequence motif in the enhancer. These data suggest a potential side effect of cAMP-elevating drugs such as PTX.