The Self Defense of Cytomegalovirus—In This Case the Lawyer is no Fool

Cytomegalovirus (CMV) is a member of the herpes virus family (1). In the immunocompromised solid organ transplant patient, CMV disease may be the result of reactivation of the recipient’s latent infection or through viral transmission from the donor organ (2). There is a large body of literature that suggests that CMV infection, either latent or active, may play a role in the chronic inflammatory state known as chronic rejection. Clearly a better understanding of CMV infection in both productive and latent states is important to further define the therapeutic approaches. Part of that understanding may come from observations of the host response to active viral replication. However, there may also be viral products playing a role in the immunological response to viral replication. In the current issue, Sadeghi and colleagues make an observational study of cytokine changes before, during, and after viremia in renal transplant patients. The study makes several interesting conclusions regarding the balance between Th1 and Th2 cytokines associated with CMV DNA detection, and provides a more comprehensive look at both cytokine production and cytokine changes over time in association with CMV DNA detectable states. With regards to cytokine production episodes of detectable CMV DNA, interferon (IFN) levels increase to some degree. Other inflammatory modulators also increase, including interleukin-2 receptor (IL-2R). But there is another interesting observation that was not noted by the authors: there is a difference in the absolute levels of IFN between the CMV DNA positive patients and the CVM DNA-negative patients. Patients who never demonstrated detectable CMV DNA had IFN levels 40% to 50% higher than those who were CMV-positive, but had relatively comparable IL-10 levels. The authors propose that this may be related to the effect of the virus on the balance of Th1 versus Th2 cytokines. However, another hypothesis is also plausible—this may be an effect of viral cytokine homologues, specifically IL-10. As a potent immunosuppressive cytokine, IL-10 plays a major role in the host response to infection. It is secreted by multiple cell types and also has a wide range of pleiotrophic effects. IL-10 has been shown to inhibit the production of many cytokines, including IL-2, IFN, tumor necrosis factor and IL-1 (3). Specifically IL-10 can deactivate macrophages and prevent response to viral infection. It has been shown that CMV can induce the expression of IL-10 during infection, thus allowing for further replication of the virus and evasion of host immune responses through down-regulation of the host response. There is a growing body of literature outlining the production and effects of the viral homologue of IL-10 (cmvIL-10). First described by several groups in the early part of the decade (4, 5), the virally encoded IL-10 has been identified to interact with multiple cell targets. This homologue can compete for binding with the IL-10 receptor, despite a relatively low level of homology (4). This viral protein has been shown to inhibit proliferation of mitogen stimulated peripheral blood mononuclear cells and decrease major histocompatibility complex class I and II molecules (6). This viral cytokine has also been detected during latent infection (7) although the functional characteristics may not be fully expressed (8). Taken together, these observations provide insight into how the virus escapes detection, down-regulates host response, and allows for ongoing latency in both immunocompromised and immunosuppressed hosts. This then brings us back to the current manuscript. In trying to decipher first the effects of active viral replication, there are clearly host changes induced by the virus that down-regulate the immune response and allow for the virus to replicate and cause disease. This process may also result in more chronic effects on the transplanted organ. It is easy to imagine that CMV maintains itself through the induction of host produced immunosuppressive cytokines such as IL-10 and augments that effect with production of its own IL-10, resulting in a viral load that never completely clears but potentially becomes undetectable. Complete eradication is prevented. But of greater interest are those individuals who did not have detectable CMV DNA during the course of the study and had higher IFN levels at almost all time points but no significant differences in IL-10 levels. Is it possible that the immunosuppressive difference resides in the virus itself? Can CMV be subtyped by the amount of cmvIL-10 it produces, making a higher producer more likely to reactivate and cause disease? Would knowing this make predictions regarding chronic rejection after transplant more reliable and allow for different treatment modalities? The answers to these questions remain to be addressed. But perhaps, going forward, the additional relevant question regarding cytokine production may relate not just to what the host is producing, but also what the virus is contributing to its own defense, and seems to be smarter than its host.