Martín-Martínez 2025 — HERV dysregulation in ME+MS case responsive to rituximab

One-paragraph summary

Single-patient case report from the same Oltra-group lineage as the 2023 HERV classifier paper. A 30-year-old male diagnosed with ME/CFS, who developed MS eight years later, showed dramatic response to rituximab after systematic failure of prior treatments. Critically, the patient was HERV-W ENV-NEGATIVE — but genome-wide HERV transcriptome analysis revealed a distinct altered HERV profile. Two consequential implications: (1) HERV reactivation in chronic post-viral conditions extends beyond HERV-W ENV to other HERV elements that may carry their own pathogenic signal — meaning HERV-W-targeted therapy (temelimab) misses a subset of HERV-driven patients; (2) rituximab worked in this patient despite Fluge & Mella's earlier rituximab phase 3 in unstratified ME/CFS being negative — strongly suggesting a HERV-positive subtype within ME/CFS responds to B-cell depletion that an all-comers cohort dilutes out. This case is single-n but mechanistically important because it provides a candidate biomarker-stratified rationale for a B-cell-depletion retrial in HERV-positive ME/CFS / FM populations.

Claims as triples

• HERV_reactivation — bridges → rituximab [evidence: case-report response to rituximab in HERV-altered patient; confidence: bridging]
• HERV_K — present_in → me_cfs [inferred: the non-HERV-W altered HERVs are likely HERV-K family members; confidence: inferred]
• fm_autoimmune — bridges → me_cfs [strengthened: shared HERV mechanism with autoimmune-overlap features; confidence: bridging]

Methods note

Single-patient case report. Genome-wide HERV transcriptome analysis by high-density microarray. HERV-W ENV protein detected by ELISA/Western (negative). Authors: same Oltra group from 2023 HERV classifier paper.

Limitations

• n=1. Single-patient case reports cannot establish prevalence or causation.
• The patient also has MS, complicating attribution of rituximab response to ME/CFS vs MS axis.
• Rituximab response was clinical (treatment failure → response) without quantitative metrics in the abstract.
• Did not measure post-rituximab HERV profile to test whether HERV expression normalized.
• Preprint, not peer-reviewed.

Open questions raised

• Which specific HERV elements (HERV-K family? HERV-H? others) are altered in HERV-W-negative HERV-positive patients?
• Is there a "HERV-W-negative HERV-K-positive" subtype that responds to rituximab while HERV-W-positive patients respond to temelimab? This would mean the project should track HERV stratification at the family level, not just HERV-W presence.
• Does the rituximab response correlate with B-cell-mediated HERV antigen presentation? (Mechanistic hypothesis: B cells expressing HERV antigens drive disease; depleting them helps.)

Triangulation notes

• Important nuance for the viral-genome-modification framework: HERV-W ENV is the most-studied marker but the broader HERV transcriptome may carry the disease signal in a substantial subset of patients. The biomarker-mapping cohort should consider broader HERV profiling (microarray or RNA-seq) in addition to HERV-W ENV ELISA.
• Tensions with Fluge & Mella 2025 (daratumumab pilot): rituximab here, daratumumab there. Both target B-lineage but at different stages. Could mean: (a) HERV-W-positive patients respond to daratumumab (proximal-to-IgG); HERV-W-negative HERV-altered patients respond to rituximab (B cells expressing HERV antigens); (b) different ME/CFS subtypes respond to different B-lineage agents. Critical to disentangle in the next stratified trial design.
• Reinforces B7 (HERV reactivation ↔ FM autoimmune subtype) but expands it to include non-HERV-W HERV elements.

Bridges

• B7 (HERV ↔ autoimmune) extended: the bridge encompasses the broader HERV transcriptome, not just HERV-W ENV.
• B3 (CRPS ↔ FM via pathogenic IgG): the rituximab-responder subtype here may parallel similar B-cell-depletion responder subgroups in CRPS.