Cytomegalovirus at the crossroads of immunosenescence and oncogenesis

Abstract

Human cytomegalovirus (HCMV), whose genome is around 235 kb, is a ubiquitous human herpesvirus that infects between 40% and 95% of the population. Though HCMV infection is commonly asymptomatic and leads to subtle clinical symptoms, it can promote robust immune responses and establish lifelong latency. In addition, in immunocompromised hosts, including individuals with acquired immunodeficiency syndrome (AIDS), transplant recipients, and developing fetuses it can lead to severe diseases. Immunosenescence, well-defined as the alterations in the immune system, is linked mainly to aging and has been recently gathering considerable attention. Senescence was characterized by an elevated inflammation and hence considered a powerful contributor to “inflammaging” that is measured mainly by tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP) levels as well as latent viral infections, for instance, cytomegalovirus (CMV). Inflammaging resulted in a senescence-associated secretory phenotype (SASP). HCMV is markedly associated with accelerated aging of the immune system as well as several age-associated diseases that accumulate and subsequently deteriorate the immune responses, thus have been linked to mortality, declined vaccine efficacy, serious diseases, and tumors in the elderly. HCMV triggers or exacerbates immunosenescence; on the other hand, the weakened immune responses and inflammaging favor viral reactivation and highlight the role of HCMV in aging as well as viral-associated tumors. HCMV reactivation resulting in sequential lytic and latent viral cycles could contribute to HCMV genomic variability. Besides the oncomodulatory role and transforming capacities of HCMV, the immune-privileged tumor microenvironment has been considered the main element in tumor progression and aggressiveness. Therefore, the interplay between HCMV, immunosenescence, and cancer will aid in discovering new therapeutic approaches that target HCMV and act as immune response boosters mainly to fight cancers of poor prognosis, particularly in the elderly population.

Cellular Transformation by Human Cytomegalovirus

“…Although non-oncogenic viral infections (human respiratory syncytial virus, influenza A virus, HIV, measle virus, and dengue virus) favor senescence, most oncogenic viruses (EBV, KSHV, HBV, HCV, and MCPyV) and HCMV have been reported to trigger senescence but also to generate PGCCs [ 26 , 143 ]. Interestingly, HCMV is at the cross-road of senescence and oncogenesis [ 144 ], and as for other oncoviruses (e.g., HPV), not all individuals infected with HCMV will develop cancer and non-viral factors (lifestyle and personal immune system) could be also at play. Similar to HPV disease pathophysiology [ 145 ], although even healthy individuals might be at risk of HCMV-induced oncogenesis, immunocompromised individuals could develop persistent, treatment-refractory, and progressive HCMV-linked cancers.…”