Effect of Cytomegalovirus on Cardiac Allograft Arteriosclerosis—Indirect or Direct?

Abstract

Clinical evidence that human cytomegalovirus (HCMV) has a role in cardiac allograft arteriosclerosis comes from a study where ganciclovir treatment of heart transplant recipients delayed allograft rejection and the development of allograft arteriosclerosis (1). However, the mechanisms by which CMV enhances cardiac allograft arteriosclerosis are incompletely understood. In an article published in this issue, Streblow et al. have investigated the role of CMV-encoded chemokine receptors in cardiac allograft arteriosclerosis in a rat heart transplant model using a mutant strain of rat CMV (RCMV) that lacks the R33 open reading frame (RCMV R33) (2). The R33 chemokine receptor is a functional homologue of the HCMV encoded chemokine receptor US28. Streblow et al. have previously shown that HCMV infection of arterial smooth muscle cells (SMC) in vitro induces cellular migration that is mediated by the virally encoded chemokine receptor US28 (3).In their article, the authors show that the mutant strain RCMV R33 induces far less SMC migration than a normal RCMV strain in vitro. Also, compared to normal RCMV, the mutant strain RCMV R33 was associated with a later onset but did however, accelerate the development of cardiac allograft arteriosclerosis compared to non-infected controls. The authors showed that similar quantities of viral DNA could be observed from the allograft in mutant RCMV R33-and normal RCMV-infected recipients but the mutant RCMV R33 could not be located in the salivary glands in contrast-to-normal RCMV. Therefore, if SMC in the allograft media are heavily infected with CMV encoding US28 (in man) or R33 (in rat) or other chemokine receptors, one could think that these infected SMC would migrate to the intimal area and proliferate there causing the concentric intimal lesion seen in allograft arteriosclerosis. The findings in this study support the 'direct hypothesis' of the effect of CMV on development of cardiac allograft arteriosclerosis, that is, CMV infects SMC and causes their migration and proliferation in the vascular wall by altering the metaboly of SMC. For example, Speir et al. showed that CMV may inactivate the p53 tumor suppressor gene and CMV actively induces SMC migration in vitro (4).In our series, we have detected only a few RCMV-positive cells in allografts in vivo at any time point and the infected cells are mostly mononuclear inflammatory cells (5). Thus, we feel that CMV does not directly enhance SMC migration and proliferation to a significant extent but rather is a marked risk factor for acute rejection and has been shown to actively boost the alloimmune response. Furthermore, CMV infection-enhanced allograft arteriosclerosis may be inhibited with elevated immunosuppression, suggesting that CMV infection enhances SMC migration and allograft arteriosclerosis indirectly via strengthening the alloimmune response (6). In this article, the effect of the mutant strain RCMV R33 on acute rejection and allograft inflammation was not studied and it would have been interesting to see whether th...