Cytomegalovirus Specific T Cell Populations are Associated with Adverse Outcomes in Aging
In individuals with normal immune function, cytomegalovirus infection goes unnoticed and produces no immediately evident ill effects. It is very prevalent in the human population. By the time old age is reached, something like 90% of individuals test positive for persistent cytomegalovirus presence. Like other herpesviruses, cytomegalovirus cannot be cleared by the immune system and lurks in the body for the remainder of life. Unfortunately, it appears that the presence of cytomegalovirus does cause harm over time in older individuals, provoking the aged immune system into an ever greater focus on this one virus at the expense of retaining capacity to address other threats, one part of the bigger picture of age-related immune dysfunction. It is one that could perhaps be addressed by a suitably selective destruction of immune cells with specific molecular markers, using well established gene therapy tools, but little work has taken place on this sort of approach to therapy.
Cytomegalovirus (CMV) infection is one of the most common infections in humans, and CMV antigens are the major drivers of repetitive T-cell stimulation as a part of a well-adapted immune response in immunocompetent individuals. With higher age, the recurrent clonal expansion of CMV-specific T cells results in high frequencies of CMV-specific effector T cells. Further on, CMV seropositivity has been linked to an increased risk of developing cardiovascular diseases (CVD). Here we investigated the frequency and phenotype of CMV-specific T cells in the circulation of a population cohort of 650 individuals focusing on the age group over 60 years.
We add to previous knowledge by showing that the frequency of CMV-specific CD8+ T cells is associated with the total percentage and absolute counts of CD8+ and CD4+CD8+ double-positive T cells within leukocytes, and further with systolic blood pressure (SBP) and history of CVD. An investigation into the differentiation status of CMV-specific T cells revealed an association of higher age and increased frequencies of both effector memory (TEM) and CD27-expressing terminally differentiated effector re-expressing CD45RA (TEMRA) cells. In contrast, higher CMV-IgG titers were found to be associated with TEM and CD27- TEMRA cell frequencies. SBP significantly correlated with CMV-specific effector CD8+ T cells, which was mostly reflected by CD27- TEMRA cells.
In conclusion, within the circulating CMV-specific T cell population, different effector T-cell subtypes were associated with age, serostatus, and SBP. This suggests that it is not age or infection per se that render CMV-positive individuals susceptible to CVD, but rather the cellular immune response to CMV. Detailed immunophenotyping may identify individuals whose immune systems are strongly influenced by the response to CMV, leading to health consequences and impairing healthy aging.
It does seem like we've reached a tipping point where CMV seronegative folks should be using antiviral prophylaxis to prevent or delay for as long as possible acquition of CMV infection. A case could be made for Epstein Barr as well. There are CMV specific direct antivirals now (maribavir and letermovir) but given cost and resistance concerns, simple valacyclovir would seem a reasonable option. Protocols already exist in the setting of allo-HSCT.