The Immune Response Against Human Cytomegalovirus Links Cellular to Systemic Senescence

Abstract

Aging reflects long-term decline in physiological function and integrity. Changes arise at a variable pace governed by time-dependent and -independent mechanisms that are themselves complex, interdependent and variable. Molecular decay produces inferior cells that eventually dominate over healthy counterparts in tissues they comprise. In a form of biological entropy, progression from molecular through cellular to tissue level degeneration culminates in organ disease or dysfunction, affecting systemic health. To better understand time-independent contributors and their potential modulation, common biophysical bases for key molecular and cellular changes underlying age-related physiological deterioration must be delineated. This review addresses the potential contribution of cytomegalovirus (CMV)-driven T cell proliferation to cellular senescence and immunosenescence. We first describe molecular processes imposing cell cycle arrest, the foundation of cellular senescence, then focus on the unique distribution, phenotype and function of CMV-specific CD8+ T cells in the context of cellular senescence and “inflammaging”. Their features position CMV infection as a pathogenic accelerant of immune cell proliferation underlying immune senescence. In human immunodeficiency virus (HIV) infection, where increased inflammation and exaggerated anti-CMV immune responses accelerate immune senescence, CMV infection has emerged as a major factor in unhealthy aging. Thus, we speculate on mechanistic links between CMV-specific CD8+ T-cell expansion, immune senescence and prevalence of age-related disorders in HIV infection.

Senescence and Host–Pathogen Interactions

“…HCMV is an enveloped double stranded DNA beta herpes virus that establishes a latent infection, with periodic reactivation controlled by the host cytotoxic T lymphocytes (CTL) response in healthy individuals [53]. Continued antigen exposure as seen in the HCMV infection (hyperantigenemia) results in telomere erosion and replicative senescence, a process which occurs faster and more frequently in CD8+ cytotoxic T lymphocytes (CTL) compared to CD4+ T helper cells [54][55][56].…”

“…However, there is not a general consensus whether this phenotype is associated with reduced telomere length [57][58][59]. HCMV-specific T lymphocytes can secrete higher levels of pro-inflammatory cytokines (IFN-γ and TNF-α) upon stimulation [56], possibly contributing to the process of inflammageing, but exhibit poor proliferative responses, possibly due to the eroded feature of their telomeres.…”

Inflammaging in Endemic Areas for Infectious Diseases

“…CMV-seropositive elderly individuals have a higher chance of developing age-associated chronic inflammatory diseases, but it remains unclear whether this latent infection has only a negative impact in the longevity (206). A study by Bajwa and coworkers (217) addressed the polyfunctionality of T cells (i.e., several Tcell effector functions), a relevant quality for protection against virus and to vaccination, evaluating CMV-specific CD4+ and CD8+ T-cell responses to 19 different CMV target proteins in young and old volunteers.…”

Optimism, pessimism, and health biomarkers in older couples

“…In brief, optimists expect things to go their way and pessimists do not (Kubzansky, Kubzansky, & Maselko, 2004). One of the suggested mechanisms linking optimism/pessimism to cardiovascular health have been cardiovascular‐related biomarkers (e.g., C‐reactive protein [CRP] and high‐density lipoprotein [HDL])(Heath & Grant, 2020; Lagrand et al ., 1999). However, few consistent relationships between optimism/pessimism and these biomarkers have emerged.…”