Cytomegalovirus, an old enemy to fight. How ?

Cytomegalovirus (CMV) is a double-stranded DNA virus belonging to the herpesvirus family (HHV5). In the vast majority of cases, it causes a benign or asymptomatic disease. On the other hand, it causes severe disease in the fetus and in immunocompromised individuals. The virus is persistent, and replication is sporadically reactive. Around 60% of humanity is infected with CMV. Infection occurs through secretions. Epithelial and endothelial cells, monocytes and macrophages are the main cellular targets. Latent infection is likely to occur in monocytes and hematopoietic progenitors. Among the cells involved in the anti-CMV immune response, we should mention the role of Natural Killer (NK) lymphocytes, which are activated in particular by recognition of the HLA E molecule, probably associated with a stabilizing peptide derived from CMV. NKG2C is the activating receptor involved. Other signals contribute to NK cell activation, with NK cells acting as effectors of anti-CMV immunity through the production of interferon γ and cytotoxicity of infected cells. T lymphocytes play an essential protective role against CMV, in particular through their cytotoxic function. Severe forms of CMV infection in transplant patients can thus be controlled by adoptive immunotherapy with anti-CMV T lymphocytes. Detection of anti-CMV T lymphocytes in blood using tetramers shows that these cells represent a significant fraction of the T population (around 9-10% of memory T cells), indicating the role of chronic CMV infection (reactivation episodes) in the balance of immune responses. The accumulation of these cells can be observed in the form of "exhausted" T lymphocytes in the elderly, which are less effective against CMV infection. The molecular mechanisms responsible for this phenomenon, observed in other chronic viral infections, are beginning to be identified. It has also been shown that being a CMV carrier significantly alters the architecture of the immune system, as observed by comparing identical twins who are discordant for CMV infection. Mainly affected are γ/δ T lymphocytes, effector CD8 T cells and neutrophils. Surprisingly, it has been shown in humans and mice that chronic CMV infection promotes the efficacy of influenza vaccination in young adults, via a "heterologous" immunity conferred by the production of interferon γ induced by chronic CMV infection. However, it is also possible that poorly controlled chronic CMV infection (see above) may be deleterious in the elderly, due in particular to chronic infection of endothelial cells, the resulting inflammation and an increased risk of vascular pathologies. CMV infection represents an illustrative model of the possible consequences of chronic infection on the balance of the immune system in general.