Herpesviruses and the Hayflick Limit In Vivo

How should we assess the medical significance of a virus that infects many persons but seems innocuous? Take cytomegalovirus (CMV) as an example; most of the world’s adults are seropositive without any symptoms they can attribute to this infection; so should we dismiss CMV as an unimportant pathogen? Before doing so, we should acknowledge that subjective assessments of disease associations reported by patients can be misleading. For example, persons who smoke cigarettes may appear to be well at the time they are interviewed and those with primary human immunodeficiency virus (HIV) infection are often without overt symptoms. In both cases, long-term follow-up was required to determine the full clinical significance of these conditions. What has been revealed by the equivalent studies for CMV? Stored samples from the US National Health and Nutrition Examination Survey (NHANES) cohort III (1988–1994) were tested for CMV immunoglobulin (Ig) G antibodies, and findings were epidemiologically typical, with 67% of the adult population seropositive [1]. Nevertheless, linkage to death certification showed that, after a median 13.7-year follow-up from the initial serologic assessment, the mortality rate was significantly higher in those who were CMV seropositive than in those who were seronegative. The effect was attenuated by controlling for risk factors, including diabetes, smoking, and obesity, but it remained significant, with a relative hazard for death of 1.19 (that is, a 19% relative increase in mortality). This strikingly large effect prompted investigators from a second large population cohort in the United Kingdom to retrieve their serum samples and test for CMV IgG. They reported that, after a mean follow-up of 14.3 years, the 59% of the population who were CMV seropositive had a very similar relative hazard of 1.16 for death, after controlling for established risk factors [2]. In both studies, excess deaths were attributed to cardiovascular disease and to cancer [1, 2] Is it plausible that this association is causal? Are there any known mechanisms that might link asymptomatic CMV infection to an excess of deaths? Is there evidence of a similar association with other herpesviruses, or is CMV unique among that virus family? Remarkably, there several biologic phenomena that might explain such an association. CMV persists lifelong by hiding from the immune system [3]. It does this by expressing its immune evasion genes so that infected cells remain invisible to the immune system, allowing CMV to persist in sanctuary sites within the body [4, 5]. Some immune evasion genes provide decoy signals to natural killer (NK) cells and macrophages equivalent to those on healthy host cells, while others interfere with the stress signals that would otherwise stimulate an NK attack on cells whose biochemistry has been hijacked by a virus [4]. Many of these signals work through the HLA class I system, either by interfering with normal display of these proteins at the cell surface or by increasing display of inhibitory molecules, such as HLA-E [6]. The net effect is that the number of T cells that become committed to searching for CMV sanctuary sites increases as we age and acquire the TEMRA phenotype (T-effector cells reexpressing the RA marker classically associated with naive rather than memory cells) [7–9]. Likewise, the surface proteins expressed by NK cells become changed to express phenotypic markers that can be detected readily [10–12]. It is not clear whether all these changes are driven by a small number of sanctuary sites established during primary infection or whether periodic reactivations of latent virus or reinfections with different strains of CMV are also required. Nevertheless, after years or decades of clinically silent CMV infection, the immune system commits more resources to CMV than to all the other viruses an elderly person has encountered in his or her life [13]. This has 3 major potential effects: the excess of immune cells could contribute to chronic inflammatory diseases such as atherosclerosis; the relative lack of naive T cells could impair the ability of elderly persons to respond to new antigens of pathogens, including those found in vaccines; and the normal immune surveillance function of these cells could be impaired. Death would be attributed to atherosclerosis in the first scenario, to influenza or pneumococcal disease in the second scenario and to cancer in the third scenario, without recognizing the contribution made by underlying CMV infection. Put bluntly, physicians caring for elderly persons may currently be writing incomplete death certificates AQ1