Viral latency as a driver of epigenetic clock dysregulation and immune aging in cancer development

Abstract

Viral latency represents a complex and dynamic balance between persistent viral genomes and the host’s immune system, profoundly influencing cellular aging and increasing the risk of cancer through epigenetic reprogramming. This review examines the interconnected mechanisms linking viral latency, epigenetic alterations, and immune system aging, emphasizing their combined contribution to malignancy development. Persistent viral infections, such as those caused by Epstein-Barr virus, human cytomegalovirus, human papillomavirus, and human immunodeficiency virus, disrupt the host’s epigenetic machinery, leading to abnormal DNA methylation, histone modification, and chromatin remodeling. These changes accelerate biological aging and silence tumor suppressor genes, creating cellular environment that favors uncontrolled proliferation. At the same time, chronic immune activation and T-cell exhaustion generate a state of persistent inflammation and immunosuppression that promotes cancer initiation and progression. The review integrates findings from molecular, cellular, and epidemiological studies to highlight key signaling pathways, including nuclear factor kappa B, signal transducer and activator of transcription 3, mechanistic target of rapamycin, and sirtuin pathways, which mediate the interaction between viral persistence and host epigenetic aging. Therapeutic implications are discussed, focusing on the potential use of immune checkpoint inhibitors and biomarker-based precision strategies to counteract virus-associated carcinogenesis. Key research gaps have also been identified, including the need for longitudinal, multi-omic studies to distinguish viral-specific effects from host aging and lifestyle factors. This review provides an integrative framework for understanding how viral latency accelerates biological aging and increases cancer risk, highlighting opportunities for early detection, prevention, and targeted therapeutic interventions.

Keywords

Epigenetic clock / Viral latency / Immunosenescence / DNA methylation / Aging / Oncogenesis / Epigenetic drift / Viral reprogramming

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