Expression of HERV Genes as Possible Biomarker and Target in Neurodegenerative Diseases.

Antonina Dolei,Claudia Piu,Caterina Serra,Gabriele Ibba

doi:10.3390/ijms20153706

Abstract

Human endogenous retroviruses (HERVs) are genetic parasites, in-between genetics and environment. Few HERVs retain some coding capability. Sometimes, the host has the advantage of some HERV genes; conversely, HERVs may contribute to pathogenesis. The expression of HERVs depends on several factors, and is regulated epigenetically by stimuli such as inflammation, viral and microbial infections, etc. Increased expression of HERVs occurs in physiological and pathological conditions, in one or more body sites. Several diseases have been attributed to one or more HERVs, particularly neurological diseases. The key problem is to differentiate the expression of a HERV as cause or effect of a disease. To be used as a biomarker, a correlation between the expression of a certain HERV and the disease onset and/or behavior must be found. The greater challenge is to establish a pathogenic role. The criteria defining causal connections between HERVs and diseases include the development of animal models, and disease modulation in humans, by anti-HERV therapeutic antibody. So far, statistically significant correlations between HERVs and diseases have been achieved for HERV-W and multiple sclerosis; disease reproduction in transgenic animals was achieved for HERV-W and multiple sclerosis, and for HERV-K and amyotrophic lateral sclerosis. Clinical trials for both diseases are in progress.

Highlights

The human genome is, on average, composed of 8% human endogenous retroviruses (HERVs) [1], which, in some way, are entities in-between genetics and environment [2]
In a blind ten-year follow up from the onset of MS patients with similar features, but different for HERV-W/MSRV positivity in the cerebrospinal fluid (CSF), we found that the above CSF positivity at MS onset was related to poor prognosis
In a longitudinal evaluation of MS patients, undergoing efficacious therapy with interferonβ, we found that HERV-W/MSRV viremia fell rapidly below detection limits

Summary

Introduction

The human genome is, on average, composed of 8% human endogenous retroviruses (HERVs) [1], which, in some way, are entities in-between genetics and environment [2]. The presence of extracellular MSRV particles, and the expression of HERV-W/MSRVenv and Syncytin-1 transcripts have been detected repeatedly and independently, by several groups, in blood, brain and CSF of MS patients from different Caucasian populations, and found to be increased with respect to both healthy and pathological controls, as reviewed in [2,3,14]. Our findings were confirmed by an independent study, which observed a significant decrease in anti-HERV-Wenv and anti-HERV-Henv antibody reactivity, in relationship to interferonβ therapy, closely linked to efficacy of therapy/low disease activity [32] In another longitudinal study, we showed that Natalizumab (a humanized monoclonal antibody highly effective against relapsing-remitting MS) strongly reduces the expression of HERV-W/MSRV/Syncytin-1, in parallel with the clinical benefit [33]. 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HERV-K and Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis

HERV-K Expression in Vivo in ALS Patients and Controls

HERV-K as Contributor to ALS Pathogenesis

Findings

Conclusions