HERV Dysregulation in a Case of Myalgic Encephalomyelitis and Multiple Sclerosis Responsive to Rituximab

Abstract

This article summarizes the case of 30-year-old male diagnosed with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and its longitudinal follow-up, which provided a secondary diagnosis of Multiple Sclerosis (MS) eight years later. The most impactful result was his response to rituximab treatment after the systematic failure of prior treatments. Although the expression of endogenous retroviral proteins has been associated with autoimmunity, the patient did not show increased expression of the toxic protein HERV (human endogenous retrovirus)-W ENV, a target of the ongoing clinical trials with temelimab in MS and long COVID-19 cases. However, genome-wide HERV transcriptome analysis by high density microarrays clearly revealed a distinct profile in the patient's blood supportive of an altered immune system. Limitations of the study include sub-optimal frequency of magnetic resonance imaging to monitor lesion progression, and similarly for reassessment of HERV profiles after rituximab. Overall, the coincidence of HERV alterations and the impactful response to rituximab presents the possibility of additional, more specific, therapeutic targets encoded by other HERV elements yet to be discovered.

Keywords: Epstein–Barr Virus (EBV); Multiple Sclerosis (MS); Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); autoimmunity; human endogenous retrovirus (HERV); rituximab.

Figure 1

Magnetic resonance imaging (MRI) of the brain and spinal cord of the patient described in the clinical case, at age 31. Two subtle lesions can be observed in T2 sequences of the cervical spinal cord at the level of C3, as indicated with a red arrow (A) and in the white matter (WM) of the brain at the level of the temporal horn of the left lateral ventricle, pointed with a red arrow (B). Image obtained in FLAIR sequence, which enhances the lesions in WM (C), as indicated with a red arrow. The images were obtained in a 3-Tesla MRI (General Electric, Signa HDx, Boston, MA, USA).

Figure 2

HERV-W envelope (ENV) antigenemia in control cases (n = 10), ME/CFS (n = 15) and post-COVID-19 condition subjects (n = 26). Levels of HERV-W ENV protein in plasma are shown as the mean area under the curve (AUC), as formerly described [34]. HERV-W ENV protein level in plasma is highlighted in blue for the study case. The dotted horizontal line indicates the cutoff minimum value to be considered positive.

Figure 3

HERV clustering (A) and principal component analysis (B) of the ME/CFS male case reported in this study, along with 8 female ME/CFS cases and 9 healthy volunteer samples. Analysis includes all HERV probes of custom HERV-V3 arrays [36], displaying significant differential expression between ME/CFS and healthy control groups (FDR < 0.1 and |log2FC| > 1). Clustering heatmap was built with pheatmap [37] and PCA with the FactoMineR package [38].