Cytomegalovirus as an immunomodulator across the lifespan

Abstract

Human cytomegalovirus (HCMV) is a nearly ubiquitous β-herpesvirus that establishes latent infection in the majority of the world's population. HCMV infection profoundly influences the host immune system and, perhaps more than any other human pathogen, has been shown to create a lasting imprint on human T and NK cell compartments. HCMV-seropositivity has been associated with both beneficial effects, such as increased vaccine responsiveness or heterologous protection against infections, and deleterious effects, such as pathological neurodevelopmental sequelae from congenital infection in utero and cumulative damage from chronic lifelong latency into old age. The significance of many of these associations is unclear, as studies into the causal mechanisms linking HCMV and these disease outcomes are lacking; however, HCMV-mediated changes to the immune system may play a key role. This review examines how HCMV impacts the host immune system in an age-dependent manner with important implications for human immunophenotypes and long-term disease risk.

Figure 1.. Impact of HCMV on health and disease across the lifespan.

A. HCMV-infection in utero is associated with neurodevelopmental delay, sensorineural hearing loss, and increased cancer risk (depicted as brain/neuronal cells/inner ear and pre-leukemic clone), which may be due to the negative impact of pro-inflammatory immune responses in utero on development; B. HCMV-seropositivity is associated with improved influenza vaccine responsiveness and cross-pathogen protection in youth (illustrated by bacterium, vaccine syringe, and influenza virus), as immune activation and priming in the setting of HCMV infection may boost vaccine responsiveness and heterologous pathogen protection; C. HCMV-seropositivity is associated with increased mortality, cardiovascular disease, and cancer in elderly adults (left demonstrating coronary artery disease/atherosclerosis/vascular dysfunction and right depicting tumorigenesis/glioblastoma/colorectal cancer), which may be due to immune-mediated changes in the host resulting from chronic antigenic stimulation/latent HCMV reactivation. HCMV = human cytomegalovirus. Created with BioRender.

Figure 2.. Imprint of HCMV on human immune cell compartments.

HCMV induces major immunophenotypic changes in three main immune cell subsets 1) “classic” αβ T cells including CD4+ and CD8+ T cells, 2) NK cells, and 3) “innate-like” γδ T cells. These phenotypic changes are characterized by immune activation and differentiation, which may modulate disease risk over the life course. HCMV = human cytomegalovirus, TCR = T cell receptor, KIR = killer cell immunoglobulin-like receptor, TEM = effector memory T cell, TEMRA = CD45RA+ effector memory T cell. Created with BioRender.