Does a Genetic Variant Protect Against MS Relapses? What the CCR5-Δ32 Story Teaches Us About Treatment with Natalizumab

Multiple sclerosis (MS) is a complex immune-mediated disease in which the immune system mistakenly attacks the central nervous system (CNS), leading to inflammation, demyelination, and eventual axonal damage. While advances in disease-modifying therapies (DMTs) have transformed MS care, understanding the genetic and molecular factors that influence disease activity remains a central challenge in neurology.

One intriguing player in MS pathogenesis is the chemokine receptor CCR5, a protein found on the surface of immune cells that helps guide them toward sites of inflammation. A genetic variation—known as CCR5-Δ32 (a 32 base-pair deletion)—renders this receptor non-functional. Individuals with one copy of this allele express reduced CCR5 levels, while those with two copies lack CCR5 entirely. This deletion has gained attention not only in MS but also in HIV research, since CCR5 is a critical entry receptor for the virus.

A study published in Acta Neurologica Scandinavica by Møller and colleagues (2014) set out to answer an important question:

Does carrying the CCR5-Δ32 allele influence disease activity in MS patients treated with natalizumab?

Why This Question Matters
Natalizumab, an antibody therapy targeting the adhesion molecule VLA-4, is one of the most effective treatments for relapsing–remitting MS (RRMS). By blocking immune cells from crossing the blood–brain barrier, natalizumab reduces inflammatory activity in the CNS.

However, some patients still experience relapses while on treatment. This suggests that other immune pathways—including CCR5-driven cell migration—could contribute to disease activity. If CCR5-Δ32 carriers were protected from relapses even while on natalizumab, it might point toward a role for combination therapies using CCR5 antagonists alongside standard treatments.

How the Study Was Done
The researchers analyzed 212 Danish patients with RRMS receiving natalizumab at Copenhagen University Hospital. Each patient was genotyped to determine whether they carried the CCR5-Δ32 deletion.

73.6% had two wild-type (normal) alleles

24.1% were heterozygous (one deletion allele)

2.4% were homozygous (two deletion alleles)

Patients were followed prospectively for at least 12 months. Clinical outcomes included:

Annualized relapse rate (ARR)


Expanded Disability Status Scale (EDSS) scores

Multiple Sclerosis Severity Score (MSSS), which corrects EDSS for disease duration

Key Findings
No significant effect on relapse rates

CCR5-Δ32 carriers did not experience fewer relapses compared with wild-type patients, either before starting natalizumab or during the first 48 weeks of treatment.

Lower disease severity scores at baseline

Carriers of CCR5-Δ32 had significantly lower MSSS values (4.6 vs. 5.4, P = 0.031), suggesting a milder disease course overall.

EDSS scores trended lower as well but did not reach statistical significance.

Trend toward longer relapse-free periods

Kaplan–Meier analysis showed that carriers had slightly longer relapse-free survival during natalizumab therapy, but the difference was not statistically significant.

What Does This Mean?
The study suggests that CCR5-Δ32 does not provide additional protection against relapses in patients treated with natalizumab. In other words, once natalizumab effectively blocks the VLA-4 pathway, the presence or absence of CCR5 seems less relevant for short-term relapse risk.

However, the finding that CCR5-Δ32 carriers had lower MSSS scores at baseline supports previous reports linking this genetic variant to a generally milder disease trajectory in untreated MS. This aligns with the idea that CCR5 contributes to immune cell recruitment into the CNS, but its role may be masked or diminished under potent therapies like natalizumab.

Why It Matters Beyond MS
This research highlights two broader themes in neuroimmunology and genetics:

Redundancy in immune pathways: Even when one pathway (VLA-4) is blocked, others (such as CCR6 for Th17 cells) can drive inflammation. This explains why no single therapy completely halts disease activity. Limits of genetic biomarkers: While CCR5-Δ32 is associated with MS disease course, it does not appear to predict treatment response to natalizumab. Thus, at present, CCR5 genotyping is not a useful prognostic tool in clinical practice. The Take-Home Message
The CCR5-Δ32 deletion may still influence the long-term severity of MS, but it does not reduce relapse risk in patients treated with natalizumab. This finding tempers enthusiasm for CCR5 antagonists as combination partners with natalizumab but underscores the importance of investigating genetic factors in MS progression. As the authors note, further studies—particularly in untreated MS patients—are needed to clarify CCR5’s role in disease pathogenesis. For now, CCR5-Δ32 remains an intriguing genetic marker of MS biology, but not a practical predictor of treatment outcomes. Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Møller, M., Søndergaard, H. B., Koch‐Henriksen, N., Sorensen, P. S., Sellebjerg, F., & Oturai, A. B. (2014). The chemokine receptor CCR 5 Δ32 allele in natalizumab‐treated multiple sclerosis. Acta Neurologica Scandinavica, 129(1), 27-31.