Vitamin D and antivirals in Post-Polio Syndrome

​Hung Van Le*
Biologics & Drug Targets, ProSci LLC, Rockaway, The United States
ORCID
https://orcid.org/0000-0002-6913-2373 (Hung Van Le)

Abstract
 
Post-polio syndrome (PPS) is a progressive neuromuscular disorder that affects a substantial proportion of long-term survivors of poliomyelitis. Traditionally viewed as a consequence of motor unit exhaustion, PPS is increasingly recognized as a multifactorial condition involving neurodegeneration, chronic low-grade inflammation, and, more recently, persistent low-level poliovirus infection. These emerging insights point to a more complex disease model that integrates viral persistence, impaired humoral immunity, and metabolic stress in compensatory motor units.
 
Vitamin D, a pleiotropic secosteroid hormone, has been implicated in several biological processes relevant to PPS, including immune regulation, mitochondrial function, and muscle physiology. Recent findings indicate that vitamin D deficiency is common in PPS patients and may contribute to impaired immune competence and disease progression. While vitamin D does not directly target the primary neurodegenerative process, it may enhance neuromuscular resilience through immunomodulatory and metabolic effects.
 
This review examines the mechanistic intersections between vitamin D signaling and PPS pathophysiology, with particular emphasis on immune function, mitochondrial energetics, and neuromuscular junction stability. It further discusses the clinical role of vitamin D as a supportive intervention and evaluates the potential need for antiviral strategies considering evidence for persistent poliovirus infection. A multimodal therapeutic approach combining antiviral therapy, immune optimization, and metabolic support is proposed as a rational framework for future PPS management.

Introduction
 
Post-polio syndrome (PPS) is a late-onset neurological disorder that affects individuals decades after recovery from acute poliomyelitis caused by Poliovirus. Clinically, PPS is characterized by new or progressive muscle weakness, fatigue, pain, and functional decline following a prolonged period of neurological stability. The syndrome typically emerges 15 to 40 years after the initial infection and represents one of the most significant long-term complications of the global poliomyelitis epidemics of the 20th century.
 
Although the incidence of acute poliomyelitis has declined dramatically due to widespread vaccination programs, the population of polio survivors remains substantial. Current estimates suggest that 15–20 million individuals worldwide are living with the sequelae of prior poliovirus infection [1], of whom approximately 20–85% may develop PPS depending on diagnostic criteria [2]. As this population ages, PPS represents an increasing clinical and public health challenge, particularly in regions with historically high poliomyelitis burden.
 
 
Currently, there is no disease-modifying therapy for PPS. Management remains largely supportive and includes physical rehabilitation, with carefully tailored exercise programs to optimize motor unit function while avoiding overuse, symptomatic treatment for pain, fatigue, and sleep disturbances, and orthotic support and assistive devices to improve mobility. Among pharmacological approaches, intravenous immunoglobulin (IVIG) has shown modest benefits in selected patients, particularly in reducing pain and inflammatory markers, although its effects on muscle strength and long-term progression remain limited.
 
In this context of limited therapeutic options, there is increasing interest in interventions that can enhance systemic resilience rather than directly reverse neuronal loss. Vitamin D has attracted attention due to its broad biological activity, including immunomodulatory, metabolic, and neuromuscular effects. Notably, recent studies have identified a high prevalence of vitamin D deficiency in PPS patients, raising the possibility that it may contribute to disease pathophysiology rather than merely reflect lifestyle factors.
 
This review aims to integrate current knowledge on PPS with emerging insights into vitamin D biology and antiviral strategies. By examining the intersections between viral persistence, immune function, and neuromuscular degeneration, it seeks to propose a more comprehensive framework for understanding and managing PPS.

Pathophysiology of Post-Polio Syndrome: from motor unit failure to persistent viral signaling
 
Post-polio syndrome (PPS) is classically explained by progressive failure of enlarged motor units that compensated for the initial loss of anterior horn cells after acute poliomyelitis. Over decades, these metabolically stressed neurons undergo distal degeneration, leading to neuromuscular junction (NMJ) instability and denervation [3]. However, this “purely degenerative” view has been challenged by accumulating immunological data. Studies have demonstrated elevated cytokines in cerebrospinal fluid and blood, suggesting chronic low-grade inflammation [4-8].
 
This inflammatory component is substantially strengthened by recent work from Toniolo et al. [9] who reported evidence consistent with persistent low-level Poliovirus infection in long-term polio survivors with PPS. The evidence came from co-culturing PPS-derived samples, including peripheral blood leukocytes, cerebrospinal fluid, duodenal biopsy specimens, and skeletal muscle fragments, with poliovirus-susceptible cell lines. Poliovirus was then detected by RT-PCR in cell culture supernatants and by immunofluorescence in the cultured cell monolayers. This work was built on earlier studies by Leparc-Goffart et al. [10] and Julien et al. [11], which had identified poliovirus in the CSF of a smaller group of PPS patients using RT-PCR.
 
The observed persistent infection supports a model in which ongoing viral persistence may drive chronic immune activation, rather than inflammation being purely secondary. The authors further described humoral immune deficiencies in PPS patients, altered neutralizing antibody profiles, and a high prevalence of vitamin D deficiency [12]. Together, these findings suggest that PPS may involve a triad of residual viral persistence, inadequate humoral immune control, and chronic low-grade inflammation. The available evidence reframes PPS as a hybrid condition, combining neurodegeneration, immune dysregulation, and possible viral persistence.  

Relevance of Vitamin D in PPS
 
The prevalence of vitamin D deficiency raises questions about its ultimate role in the etiology of PPS. It could simply be a by-product of patients’ lifestyle (poor diet, inadequate mobility and physical activities, and limited sun exposure), or alternatively it could be a bona fide risk factor.  A combination of both could be plausible as well. As an established pleiotropic modulator of multiple pathways [13] vitamin D could be uniquely positioned to affect the development of PPS. How vitamin D signaling intersects with PPS pathways is explored below.
 
Immunomodulation and antiviral defense. Vitamin D signaling suppresses pro-inflammatory T helper 1 responses and reduces IFN-γ production [14]. Beyond dampening inflammation, vitamin D also enhances innate immune responses, supports antimicrobial peptide production, and modulates B cell function. In the context of the finding by Toniolo et al. [9,12], this is particularly relevant since  vitamin D deficiency may exacerbate impaired humoral immunity, potentially allowing persistent poliovirus activity. Thus, vitamin D may not only reduce inflammation but also improve immune competence against residual viral antigenic stimulation.
 
Muscle and mitochondrial energetics. Vitamin D influences skeletal muscle through improved mitochondrial oxidative function [15] and regulation of mitochondrial dynamics and respiration [16]. Given that PPS involves fatigable muscle and metabolically stressed motor units, vitamin D may enhance bioenergetic resilience, even if it does not halt neuronal loss.
 
Neuromuscular junction stability and mitochondrial energetics. The progressive functional decline observed in Post-Polio Syndrome is closely linked to instability of the neuromuscular junction (NMJ), which represents the final common pathway of motor neuron degeneration. In PPS, surviving motor neurons form enlarged motor units that are metabolically overextended. Over time, this leads to distal axonal degeneration, impaired synaptic maintenance, and failure of reinnervation, with NMJ dysfunction preceding overt muscle fiber loss.
 
A critical but often underemphasized aspect of NMJ stability is local energy supply. Maintenance of synaptic transmission, vesicle recycling, and ion homeostasis requires tightly regulated ATP production. This demand is met by mitochondria localized at both pre- and postsynaptic compartments, whose function is essential for sustaining neuromuscular signaling. In aging and neurodegenerative conditions, impairment of mitochondrial function—rather than sheer mitochondrial number—has been implicated as a limiting factor in synaptic resilience.
 
Vitamin D has been shown to influence mitochondrial biology at multiple levels, including enhancement of oxidative phosphorylation, modulation of mitochondrial dynamics, and regulation of transcriptional programs involving PGC-1α [15,16]. Although there is no direct evidence that vitamin D regulates axonal mitochondrial transport or synapse-specific mitochondrial targeting, its effects on mitochondrial efficiency and cellular energetics provide a plausible mechanism for improving NMJ stability under conditions of metabolic stress.
 
In this context, vitamin D may contribute to functional preservation of neuromuscular transmission by improving ATP availability in muscle and possibly nerve terminals, reducing oxidative stress that destabilizes synaptic structures, and supporting the metabolic demands of enlarged motor units. This interpretation aligns with the broader view of PPS as a disorder of metabolic exhaustion of compensatory motor units, where interventions that enhance bioenergetic capacity may delay functional decline.
 
Collectively, these observations indicate that vitamin D may enhance the metabolic stability of existing synapses, thereby slowing functional deterioration.

Clinical positioning: supplementation vs therapeutic dosing
 
This leads to an important clinical consideration: in what context should vitamin D be used in PPS?
 
As a nutritional supplement, maintaining adequate serum 25-hydroxyvitamin D levels (50-125 nmoles/L) is clearly warranted. PPS patients are at increased risk of deficiency due to reduced mobility and sun exposure, and correction of deficiency supports bone health, muscle function, and overall metabolic stability.
 
The use of high-dose vitamin D as a therapeutic intervention remains uncertain. While high-dose regimens (100,000 IU cholecalciferol, every two weeks for 24 months) have shown benefits in Multiple in Sclerosis [17] and potentially in upper respiratory viral infections [18-20], there is currently no direct clinical evidence supporting such an approach in PPS. Moreover, vitamin D exhibits dose-dependent effects, and excessive supplementation may not yield proportional benefit.
 
A more coherent approach is to incorporate vitamin D into a multimodal management strategy, alongside targeted physical therapy to optimize motor unit function, adequate protein and caloric intake, and interventions aimed at preserving mitochondrial and neuromuscular health. The goal here is to remove an exacerbating factor while hoping for disease modifications resulting from a beneficial effect on immune competence, muscle function, and bone health. The role of vitamin D supplementation in PPS is only supportive and there is clearly a need to look beyond seeking curative treatment.

Therapeutic implications: beyond vitamin D 
 
Rationale for antiviral therapy. Evidence of persistent poliovirus infection and defective replication [10,11,9] supports consideration of antiviral therapy in PPS. Combined with physical rehabilitation and the immune and metabolic support potentially provided by vitamin D, an antiviral component could help form a more mechanistically comprehensive treatment strategy. However, no antiviral drugs are currently approved specifically for poliovirus, and historical drug-development efforts were limited in part by the success of global polio vaccination programs.
 
Current development landscape. Momentum in the field has been sustained by the Polio Antivirals Initiative (PAI), which aims to develop therapies that reduce vaccine-derived poliovirus shedding in immunodeficient recipients of oral polio vaccines and mitigate the risk of prolonged excretion in a post-eradication setting. Current discovery efforts focus on four broad approaches: inhibitors of the viral capsid, viral protease, and RNA replication, as well as agents targeting host factors required for replication [21, 22].
 
Capsid inhibitors. Pleconaril and pocapavir are the most advanced candidates, having reached human studies in vaccine-derived poliovirus infection and oral poliovirus vaccine challenge models [23-27]. Pocapavir is also available for compassionate use through its developer, ViroDefense, or via the PAI.
 
RNA-replication inhibitors. Ribavirin, a broad-spectrum inhibitor of viral RNA replication, has been used compassionately in a patient with vaccine-derived poliovirus infection but did not clear the virus [25]. In contrast, remdesivir was associated with viral clearance in that same patient [28]. Remdesivir (Veklury), a nucleoside analog widely used during the COVID-19 pandemic as an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase, therefore represents an intriguing candidate for further study in persistent poliovirus infection.
 
That signal should be interpreted cautiously: the remdesivir evidence is currently limited to a single case report and has not yet been independently replicated. Even so, its availability and established clinical safety profile make it a reasonable high-priority option for off-label compassionate use in carefully selected patients with documented persistent poliovirus infection and shedding.
 
Other inhibitors and future directions. All known poliovirus protease inhibitors and agents targeting host factors remain at the preclinical stage [21,22]. Nevertheless, recent findings on persistent infection, together with renewed progress in antiviral development, provide a strong rationale for reinvigorating this field. From a compassionate-care perspective, such efforts are justified by the potentially large global burden.

Conclusion
 
Vitamin D is best understood as a pleiotropic adjunct in PPS, which may improve immune balance, mitochondrial function, and possibly NMJ resilience. Its deficiency, common in PPS, should be corrected as part of standard care. However, evidence for high-dose therapeutic use remains lacking and its effects are supportive rather than disease-modifying. In light of emerging evidence for persistent poliovirus infection and immune dysregulation, future therapeutic strategies should expand beyond supplementation alone. A combination approach including antiviral therapy, immune optimization, and metabolic support may offer the most rational path forward in PPS management.

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Acknowledgment: Dr. NhuCo Lethi provided the initial inspiration for this article on PPS.