Cytomegalovirus Research in Immune Senescence Comes of Age

Researchers are these days feeling more confident in the identification of cytomegalovirus as a significant cause of immune system dysfunction in aging, as the conference report here illustrates. We might hope that this growing interest in cytomegalovirus in the context of aging will lead to more funding of means to repair the situation, aiming to restore some of the youthful capability to respond to pathogens and destroy potentially dangerous cells.

The immune system is an adaptable machine, but one with limits. In adults new immune cells are generated at a very slow pace in comparison to the overall count of such cells in circulation. This effectively produces what looks a lot like a limit on the number of immune cells. As the years pass, that limited population is increasingly taken over by endlessly duplicated memory cells specialized to cytomegalovirus. Uselessly specialized, as the immune system cannot effectively clear this virus from the body. Near everyone is infected by cytomegalovirus by the time old age is reached, but aside from its insidious long-term effects on the immune system, it causes no noticeable problems in the vast majority of people. Thus approaches to tackling it have not been given any great priority in the medical science community of past decades. When much of the immune system is overtaken by cytomegalovirus-specific cells, however, that leaves all too little room for cells capable of productively carrying out other functions, and the result is a failing immune system, characteristic of the old.

The best near-team approach to this problem is probably some form of selective destruction of the unwanted specialized immune cells, in order to free up capacity. That can be coupled with the generation of replacement immune cells from a patient cell sample, returned to the body to quickly make up the numbers. This is a very plausible goal, given the various trials and technology demonstrations of immune cell clearance for therapeutic purposes. The greatest challenge involved is to develop targeted cell destruction approaches that are safe and have minimal side effects for the patient, in comparison to the damaging pharmaceuticals used to date in human trials.

Nearly two decades ago, two key findings connected cytomegalovirus (CMV) with immune senescence. In 1999, researchers showed that CMV-positive and -negative humans exhibit dramatically different T cell subset ratios and that the effect seems to be increasing with aging. Around the same time, others described "memory inflation" driven by CMV in mice. Since then, numerous studies have been published investigating the associations between human, non-human primate or murine CMV with their respective hosts in the course of aging. The interest in the topic has been so sustained that it led to the establishment of CMV and Immunosenescence Workshops. This overview summarizes the state of the field before and the discussions at the 6th International CMV and Immunosenescence Workshop.

CMV, a member of beta-herpesvirus family, is the largest human virus. As is the case for other herpesviruses, following a brief acute infection period that elicits a typical CD8 T cell response, as well as CD4 and B cell responses, CMV establishes persistence that includes latency. Persistence/latency is established in reservoir cells that are distributed broadly across the organism. However, it is clear that the primary CMV infection is followed by a period of viral shedding and it remains unclear whether the virus, that is a master in immune evasion, ever really is truly latent in all its reservoirs or whether some cells produce it as a smoldering infection at low levels at most, if not all times. As a consequence, a large population of CMV-specific CD8, and to a lesser extent, CD4 T cells, is generated in response to cycles of viral reactivation (aptly called memory inflation). How exactly this memory inflation impacts the ability of an older immune system to function and provide defense against other infections is one of the key topics of interest.

The 6th International Workshop on CMV and Immunosenescence was organized with a primary goal to fill a gap identified at several recent meetings. Specifically, in addition to the topics reviewed above from the fifth workshop, it was felt that stronger attention must be focused on the biology of the virus itself and on its interactions with the host in the course of latency and reactivation. In fact, one of the greatest weaknesses of research into HCMV and immunosenescence comes from our inability to control and measure the state of viral activity. Another area of major interest is the impact of CMV on diseases on aging - whether and how the virus may be involved in modulating frequent age-related morbidities, in particular cardiovascular diseases (CVD), where there are strong epidemiological associations between CMV infection and morbidity and mortality from CVD.


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