Retroviral Remnants in the Human Genome: Classification, Integration and Regulation

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections constituting nearly 8% of the human genome. Far from being inert genetic fossils, HERVs have co-evolved with their hosts, acquiring regulatory and functional roles that influence development, immunity and disease. In this comprehensive review, we examine the origin, evolutionary dynamics and structural diversity of HERVs, emphasising their integration, genomic organisation and mosaic recombination patterns. We further highlight how epigenetic modifications, intracellular factors such as transcriptional regulators, hormones and cytokines, and environmental influences regulate HERV expression. By synthesising current evidence linking HERV activity to immune modulation, tumourigenesis, autoimmunity and neurodegenerative processes, we provide an integrated perspective on their dual role as drivers of pathology and contributors to normal physiology. Our analysis underscores that HERVs are not only markers of past infections but also active genomic elements with potential clinical implications, from biomarker discovery to novel therapeutic targets, making their systematic investigation timely and highly relevant.