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Activation of human endogenous retroviruses and its physiological consequences

Nature Reviews Molecular Cell Biology volume 25, pages 212–222 (2024)Cite this article

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Abstract

Human endogenous retroviruses (HERVs) are abundant sequences that persist within the human genome as remnants of ancient retroviral infections. These sequences became fixed and accumulate mutations or deletions over time. HERVs have affected human evolution and physiology by providing a unique repertoire of coding and non-coding sequences to the genome. In healthy individuals, HERVs participate in immune responses, formation of syncytiotrophoblasts and cell-fate specification. In this Review, we discuss how endogenized retroviral motifs and regulatory sequences have been co-opted into human physiology and how they are tightly regulated. Infections and mutations can derail this regulation, leading to differential HERV expression, which may contribute to pathologies including neurodegeneration, pathological inflammation and oncogenesis. Emerging evidence demonstrates that HERVs are crucial to human health and represent an understudied facet of many diseases, and we therefore argue that investigating their fundamental properties could improve existing therapies and help develop novel therapeutic strategies.

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Fig. 1: The endogenization of a retrovirus.
Fig. 2: Spatiotemporal patterns of human endogenous retrovirus activity throughout development.
Fig. 3: Proposed model for human endogenous retrovirus contributions to ageing-associated neurodegeneration.
Fig. 4: Deregulation of human endogenous retroviruses in cancer.

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Authors and Affiliations

  1. Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    Nicholas Dopkins & Douglas F. Nixon

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Glossary

Dysbiosis

The state of disbalance in the composition and diversity of microorganisms that constitute the microbiota of a host organism.

Expectation–maximization

An algorithmic computational approach that iteratively defines the maximum likelihood for given estimations based on latent variables, commonly used to improve upon estimations provided by probabilistic models of data.

Inflammasome

Multisubunit complex that assemble in the cytosol in response to inflammatory stimuli. Following their assembly, inflammasomes transduce immunological signals.

Inflammatory disorders

Conditions in which unregulated and typically self-targeting inflammation contributes to pathogenesis. Inflammatory disorders generally demonstrate cyclic cascades of immune responses that further reinforce incipient inflammation.

Neurofibrillary tangles

Pathological insoluble aggregates of hyperphosphorylated tau protein in the central nervous system.

Pattern recognition receptors

Invariant innate immunity receptors that recognize and detect molecular signals that commonly arise from pathogen invasion or cellular damage.

Retrovirus-like particles

Assembled endogenous retroviral particles that are morphologically similar to an infectious retrovirus but are replication incompetent and thus non-infectious.

Superantigen

Molecules that possess nonspecific stimulatory capacity of adaptive immunity cell subsets.

Syncytiotrophoblast

A barrier layer of multinucleated epithelial cells that separates the maternal and embryonic circulatory systems.

Ty3 or mdg4

A phylogeny of LTR-possessing retroelements. The previously used nomenclature for these elements relied on the word ‘gypsy’; going forward, these elements should be referred to as ‘Ty3’ or ‘mdg4’.

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Dopkins, N., Nixon, D.F. Activation of human endogenous retroviruses and its physiological consequences. Nat Rev Mol Cell Biol 25, 212–222 (2024). https://doi.org/10.1038/s41580-023-00674-z

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