Sara van den Berg

176 Chapter 7 INTRODUCTION Primary infection with CMV results in life-long latency, but only leads to severe disease and viral dissemination in severely immunocompromised individuals. For example as individuals use immunosuppressive medication after organ transplantation or individuals with advanced and uncontrolled human immunodeficiency virus (HIV) infection. In immunocompetent individuals, CMV infection usually remains asymptomatic due responses by the humoral and cellular immune system [1-3]. In immunocompetent individuals, the virus is thought to reactivate and to activate the immune system regularly [1-3] which may explain the changes in the T-cell compartment observed with CMV infection [4]. CMV-specific antibody levels have frequently been reported to be positively associated with age [5-7]. CMV latent viral load as measured by CMV-infected monocytes [7] or whole cells [8] as well as CMV viral load in plasma [8] and urine [2] have also been shown to be higher in older adults, and are associated with CMV-specific antibody levels. CMV-specific antibody levels are often used as a measure for experienced CMV reactivation and to identify CMV‐seropositive elderly with poor control of the virus, who are at increased risk of adverse clinical outcomes [9-15]. Since most studies rely on cross-sectional data, the underlying factors influencing CMV-specific antibody levels, and in particular the role of duration of CMV infection, in fact remain unknown. Many parallels can be drawn between the well-described changes in the T-cell pool caused by CMV infection and those observed during ageing [16, 17]. Effects of CMV on the T-cell compartment [18] are in large part thought to be due to the presence of large CMV-specific T-cell expansions, which can mount up to 30% to 90% [19, 20] of the CD8+ T-cell pool in many elderly [21]. CMV-specific CD8+ memory T-cell numbers are assumed to increase over time, a process that is often referred to as ‘memory inflation’. Memory inflation is unique for CMV [22, 23] and is believed to be most prominent for CD8+ T-cells [21, 23, 24] but also observed for CD4+ T-cells [22]. However, how prolonged exposure to a chronic virus- infection like CMV enhances immune reactivity, is not well understood. Further insight in CMV-induced memory inflation is valuable in understanding the potential harmful effect of CMV upon ageing. The accumulating changes in the immune system due to prolonged exposure to CMV infection may eventually influence general health. CMV-infected individuals have been reported to have a higher prevalence of age-related conditions such as rheumatoid arthritis [25] and cardiovascular diseases [14]. Also mortality rates were higher in CMV infected individuals [26, 27] and in individuals with higher CMV-specific antibody levels [11, 15, 27]. The mechanisms underlying the relationships between CMV infection and general health outcomes are still unknown. Although several studies show a relation between CMV infection or CMV-specific antibody levels and frailty [11, 28, 29], others do not support this [30] [31]. These reported conflicting results might be explained by differences in duration of CMV infection, which is generally unknown.