Human endogenous retroviruses in neurologic disease

Abstract

Endogenous retroviruses are pathogenic – in other species than the human. Disease associations for Human Endogenous RetroViruses (HERVs) are emerging, but so far an unequivocal pathogenetic cause‐effect relationship has not been established. A role for HERVs has been proposed in neurological and neuropsychiatric diseases as diverse as multiple sclerosis (MS) and schizophrenia (SCZ). Particularly for MS, many aspects of the activation and involvement of specific HERV families (HERV‐H/F and HERV‐W/MSRV) have been reported, both for cells in the circulation and in the central nervous system. Notably envelope genes and their gene products (Envs) appear strongly associated with the disease. For SCZ, for ALS, and for HIV‐associated dementia (HAD), indications are accumulating for involvement of the HERV‐K family, and also HERV‐H/F and/or HERV‐W. Activation is reasonably a prerequisite for causality as most HERV sequences remain quiescent in non‐pathological conditions, so the importance of regulatory pathways and epigenetics involved in regulating HERV activation, derepression, and also involvement of retroviral restriction factors, is emerging. HERV‐directed antiretrovirals have potential as novel therapeutic paradigms in neurologic disease, particularly in MS. The possible protective or ameliorative effects of antiretroviral therapy in MS are substantiated by reports that treatment of HIV infection may be associated with a significantly decreased risk of MS. Further studies of HERVs, their role in neurologic diseases, and their potential as therapeutic targets are essential.

Endogenous Retroviruses: With Us and against Us

“…Multiple sclerosis (MS) is another neurological disease in which ERVs have been strongly implicated. MSRV (multiple sclerosis-associated retrovirus), a subtype of ERV-W, as well as ERV-W1 and W2 and ERV-H/F have all been linked to MS (reviewed in Christensen, 2016). One study showed significantly elevated Env antigen in serum of MS patients relative to controls, while qPCR of ERV-W in mononuclear cells from blood (PBMC) showed association with MS relative to controls (Perron et al, 2012a).…”

Geroscience: Addressing the mismatch between its exciting research opportunities, its economic imperative and its current funding crisis

“…A more heuristic hypothesis, however, would embrace the hypothesis that there may be several distinct upstream pathogenetic pathways that are driven by one or more basic mechanisms of biological aging, all of which lead to a common downstream pathway of beta amyloidosis, tauopathies and inflammation; if so, a nomenclature of “Dementias of the Alzheimer Type” (DAT) would be preferable (Martin, 2005b). Early precursors of DAT might conceivably range from nature-nature interactions and somatic mutations/epimutations that impact age-related aberrations in proteostasis (Yerbury et al, 2016) to the emergence of viral agents as a result of either immunosenescence (Shaw et al, 2010) or age-related alterations in the stability of chromatin leading to the expression of an endogenous retroviral agent (Christensen, 2016). Another argument in favor of pathogenetic heterogeneity is the common finding of mixtures of what have been considered to be distinct types of neuropathology, including frontotemporal dementia, Lewy Body dementia and multi- infarct dementia, especially for the case of older subjects (Rahimi and Kovacs, 2014).…”

The double-edged sword of (re)expression of genes by hypomethylating agents: from viral mimicry to exploitation as priming agents for targeted immune checkpoint modulation

“…It has also been suggested that younger ERVs (i.e. more recently integrated ERVs) may play a role in human diseases including neurologic diseases (reviewed in [77]) and cancer [78]. ERVs may not only be directly disease causing, but may also modulate immunity, and evidence exists indicating a general role for ERVs in the regulation of interferon (gamma) responses [79].…”