Analysis & Commentary

Burns LJ, Pooley JC, Walsh DJ, Vercellotti GM, Weber ML and Kovacs A. Intercellular adhesion molecule-1 expression in endothelial cells is activated by cytomegalovirus immediate early proteins. Transplantation 1999; 67: 137. Few viruses cause transplant physicians as much anguish as human cytomegalovirus (HCMV). Although of relatively little clinical significance in the immunocompetent host, in patients who are immunosuppressed after organ transplants, reactivation of HCMV is associated with significant morbidity and mortality. The introduction of effective anti-viral chemotherapy has been a major therapeutic advance, but it is unwise to think that HCMV is no longer of real clinical significance. In the bone marrow transplant setting, there is a realization that prophylactic use of drugs such as ganciclovir may indeed control early viral re-activation but often lead to the occurrence of late HCMV disease. In addition, such drugs are not without significant side effects such as neutropenia. One interesting feature about HCMV is that it is not year clear to what extent the pathology associated with viral reactivation is due to lytic viral replication causing cell death or is in fact secondary to immunologically mediated processes. There is increasing evidence that the latter may indeed contribute to disease. In syndromes such as CMV-associated pneumonitis, it can be difficult to isolate virus from tissue. In addition, CMV re-activation is associated with disturbances in immune homeostasis, which cannot be attributed to direct control of the virus itself. For instance, in the stem cell transplant setting, the association of CMV reactivation and graft versus host disease is well documented. In addition, after solid organ transplants, CMV reactivation is associated with serious bacterial and fungal infections, suggesting that the virus may be associated with generalized immunosuppression (1). It is against this clinical background that investigators are now paying increasing interest to the relationship between HCMV and the immune system. The picture that is emerging is that the virus possesses an impressive array of mechanisms to evade effective control of the immune system. HCMV is truly the consummate molecular parasite-capable of infecting the great majority of the human population during their lifetime. In addition, recent evidence suggests that in the state of latency the virus is actually undergoing repeated intermittent replication. It is only the constant attention of the cellular immune response that prevents excessive viral replication (2). To understand how HCMV and the immune system may have co-evolved, we have to remember the characteristics that typify successful parasitism. The parasite does not want to kill its host, as this would reduce the opportunity for dissemination. On the other hand, it must evolve strategies to evade being completely eliminated by the immune system. A delicate balance of survival must therefore be established, and this seems to be the lesson from studies of immunity to HCMV. Some features of HCMV would fit with a strategy of outright immune evasion. The ability of viral genes to down-regulate HLA class I expression and block assembly of peptide-HL:A complexes is well described and clearly impairs the ability of infected cells to present HCMV peptides to the cell surface (3). In addition, viral proteins are able to interfere with HLA class I-peptide assembly by down-regulating expression of aminopeptidases (4). An interference with intracellular signaling by HCMV gene products has recently been described which impairs HLA class II expression, although there is little evidence to date on the mechanism behind this (5). Most recently, the intriguing observation has been made that HCMV can sequester human chemokines (6). The significance of the virally encoded HLA class I homolog UL18 is less clear. The "missing-self" hypothesis for natural killer (NK) cell killing in which NK cells kill autologous targets which lack HLA class I expression has now been established. As HCMV can down-regulate HLA class I molecules and would therefore render the infected cell susceptible to lysis by NK cells, it was felt likely that the role of UL18 would be to act as a "decoy" to trick the NK cell into thinking that HLA class I was still being expressed. One report suggested that UL18 could indeed inhibit cell killing by NK cells (7), but this has been questioned by two subsequent papers suggesting that UL18 may in fact enhance killing of virally infected cells (8,9). The fact that UL18 may enhance lysis of infected cells is perplexing, but there are other features that suggest HCMV is not averse to stimulating immune responses against itself. The exact tissue specificity of latent infection is unclear, but the monocyte lineage is one reservoir (10). It appears that after appropriate stimulation, HCMV can be isolated from dendritic cells, the cells that are responsible for generating primary immune responses (11). Why HCMV should want to place itself at the center of the immune response in this way is unclear. In this issue of Transplantation, Burns et al. confirm that expression of intercellular adhesion molecule-1 (ICAM-1) is enhanced on cells following infection with HCMV (12-14). ICAM-1 is an inducible transmembrane glycoprotein that promotes cell adhesion and migration. It binds to integrins on both lymphocytes and neutrophils and its expression is enhanced by a variety of inflammatory cytokines including IL-1 and IL-6. The paper reveals that ICAM-1 expression is increased directly as a result of expression of HCMV immediate early (IE) genes and is not a secondary effect following cytokine induction. This finding has at least two important implications. First, as ICAM-1 expression is important in mediating cell to cell adhesion at the time of cell lysis by cytotoxic T lymphocytes, it suggests that the effect might be to enhance lysis of virally infected cells. In addition, because ICAM-1 is important in mediating cellular recruitment during inflammatory responses, this may explain why HCMV infection is associated with immunopathology such as graft rejection and graft versus host disease. HCMV remains a major clinical problem in clinical transplantation and we need to enhance our understanding of the relationship between the virus and our own immune system. Having spent millions of years perfecting its role as a cellular parasite, HCMV has developed a respectful relationship with the immune system. Clearly organ transplantation is an "unnatural" phenomenon and one to which the virus is not well adapted. The hope is that future collaborations between transplant physicians, immunologists, and virologists will unravel more details about this fascinating virus which will lead to further clinical advances. Paul Moss Professor of Haematology; University of Birmingham; Edgbaston; B15 2TA; U.K.