Pediatric roots of cytomegalovirus recurrence and memory inflation in the elderly

The establishment of a lifelong latent infection after resolution of primary infection is a hallmark of cytomegalovirus (CMV) biology. Primary infection with human CMV is possible any time in life, but most frequently, virus transmission occurs already perinatally or in early childhood. Many years or even decades later, severe clinical problems can result from recurrence of infectious virus by reactivation from latency in individuals who undergo immunocompromising medical treatment, for instance, transplant recipients, but also in septic patients without canonical immunosuppression, and in elderly people with a weakened immune system. The diversity of disease manifestations, such as retinitis, pneumonia, hepatitis, gastrointestinal disease, and others, has remained an enigma. In clinical routine, seropositivity for IgG antibodies against human CMV is taken to indicate latent infection and thus to define a qualitative risk of recurrence, but it is insufficient as a predictor for the quantitative risk of recurrence. Early experimental studies in the mouse model, comparing primary infection of neonatal and adult mice, led to the hypothesis that high load of latent viral genomes is a better predictor for the quantitative risk. A prolonged period of virus multiplication in the immunologically immature neonatally infected host increased the risk of virus recurrence by an enhanced copy number of latent virus genomes from which reactivation can initiate. In extension of this hypothesis, one would predict today that a higher incidence of reactivation events will also fuel the expansion of virus-specific T cells observed in the elderly, a phenomenon known as "memory inflation". Notably, the mouse model also indicated a stochastic nature of reactivation, thus offering an explanation for the diversity and organ selectivity of disease manifestations observed in patients. As the infection history is mostly undefined in humans, such predictions from the mouse model are difficult to verify by clinical investigation, and moreover, such questions were actually rarely addressed. Here, we have surveyed the existing literature for reports that may help to retrospectively relate the individual infection history to the risk of virus recurrence and recrudescent organ disease.