Viral Infections and Neurodegenerative Diseases: Reinterpreting the Crosstalk Through a Dual-Role Lens.

ingentiumby ingentium

In Discovery Literature.

Publication date: Jun 24, 2026

Neurodegenerative diseases (NDDs) are multifactorial disorders with increasing evidence implicating viral infections in their pathogenesis. However, current reviews often catalog virus-disease associations without integrating this evidence into a unified conceptual model that also accounts for the therapeutic potential of viral platforms. This review investigates recent literature to propose a “dual-role” model for viruses in NDDs. We analyze how diverse viruses (e. g., HSV-1, HIV, EBV, and SARS-CoV-2) converge on shared pathogenic pathways, including protein misfolding, chronic neuroinflammation, and mitochondrial dysfunction, across different NDDs. Paradoxically, engineered viral vectors derived from neurotropic viruses are being investigated as tools for targeted gene therapy. To address these therapeutic applications of viruses, this review also provides an in-depth report of the various viral vector technologies developed. The approaches involved in designing rationally engineered viral vectors based on various adeno-associated virus serotypes through rational design, directed evolution and machine learning strategies, as well as the lentiviral and herpes simplex virus-based platform are described. Different strategies that have been used to incorporate large and/or small payloads such as gene replacement, RNA interference, microRNA cassettes, CRISPR-based gene editing (base editing, prime editing, CRISPRa and CRISPRi) and the double AAV systems to deliver larger transgene cassette have also been reviewed. This review further includes various routes of administration including intrathecal, intracerebroventricular and convection-enhanced delivery with the use of Focused Ultrasound. The constraints imposed by the Blood-Brain Barrier are discussed, especially the approach using receptor-mediated transcytosis for crossing. The review also critically evaluates obstacles toward clinical translation of viral vectors due to various factors including immunogenicity, the presence of pre-existing neutralising antibodies and dose-dependent toxicity, illustrated by the fatal outcome of ASPIRO and DMD trials. Finally, this review concludes with other promising non-viral approaches such as lipid nanoparticle and extracellular vesicles. Future research needs include long-term studies to investigate causality and extensive safety optimization of viral vectors.

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Concepts Keywords
Immunogenicity Animals
Mitochondrial Gene Therapy Agents
Nanoparticle Genetic Therapy
Therapy Genetic Vectors
Viruses Humans
Neurodegenerative Diseases
Virus Diseases

Semantics

Type Source Name
disease MESH Viral Infections
disease MESH Neurodegenerative Diseases
pathway REACTOME Neurodegenerative Diseases
disease MESH neuroinflammation
disease MESH mitochondrial dysfunction
disease MESH herpes simplex
pathway REACTOME Translation
disease MESH DMD
drug DRUGBANK Coenzyme M
disease MESH Infectious Diseases
disease MESH Multiple sclerosis
disease MESH Japanese encephalitis
disease MESH Severe acute respiratory syndrome
disease MESH shock
disease MESH Varicella
disease MESH zoster
drug DRUGBANK Oxygen
disease MESH ALS Amyotrophic lateral sclerosis
disease MESH Frontotemporal dementia
disease MESH SLE
pathway KEGG Systemic lupus erythematosus
disease MESH syndrome
pathway KEGG Amyotrophic lateral sclerosis
disease MESH fac
drug DRUGBANK Trihexyphenidyl
drug DRUGBANK Profenamine
disease MESH tar
pathway REACTOME Apoptosis
disease MESH infection
disease MESH demyelination
drug DRUGBANK ATP
disease MESH ics
pathway REACTOME Mitophagy
disease MESH death
drug DRUGBANK Thiocolchicoside
pathway REACTOME Autophagy
disease MESH SARS CoV 2 infection
disease MESH proteinopathies
disease MESH Lipid metabolism disorders
disease MESH Polio
disease MESH mROS
pathway REACTOME Nucleotide biosynthesis
drug DRUGBANK Calcium
disease MESH OPA1
disease MESH NS3
disease MESH Myxoma
disease MESH NS1
disease MESH NS2
disease MESH Cowpox
disease MESH Fibroma
pathway KEGG Necroptosis
disease MESH Swine Fever
pathway REACTOME Pyroptosis
drug DRUGBANK N-acetylsulfanilyl chloride
pathway KEGG Ferroptosis
drug DRUGBANK L-Cysteine
drug DRUGBANK Glutathione
disease MESH GSH
drug DRUGBANK 8-cyclopentyl-1 3-dipropylxanthine
disease MESH CPX
drug DRUGBANK Deferoxamine
disease MESH TSC2
drug DRUGBANK Cidofovir
disease MESH HOPS
disease MESH Traps
disease MESH Cytokine storm
disease MESH NS6
disease MESH Thrombocytopenia
disease MESH Measles
pathway KEGG Measles
disease MESH Peste Des Petits Ruminants
disease MESH PRRs
disease MESH NOD
drug DRUGBANK Tretinoin
disease MESH melanoma
pathway KEGG Melanoma
pathway REACTOME Glycogen synthesis
disease MESH inflammation
disease MESH Vesicular Stomatitis
disease MESH VSVs
disease MESH dystrophic epidermolysis bullosa
disease MESH neurological disorders
disease MESH tic
disease MESH NS5
disease MESH ered
drug DRUGBANK Cefradine
disease MESH CED
disease MESH Parkinson’s disease
drug DRUGBANK Gold
disease MESH Huntington’s disease
drug DRUGBANK Alpha-methyltryptamine
pathway KEGG Spliceosome
disease MESH immune suppression
disease MESH X linked myotubular myopathy
disease MESH hepatic failure
disease MESH cardiac arrest
drug DRUGBANK Patisiran
disease MESH hereditary transthyretin amyloidosis
drug DRUGBANK Valaciclovir
disease MESH Alzheimer’s disease
disease MESH dementia
drug DRUGBANK Acyclovir
disease MESH Leber congenital amaurosis
disease MESH SCD
disease MESH cytomegalovirus infection
disease MESH genetic predisposition
disease MESH dis
disease MESH thrombotic microangiopathy
disease MESH genomic instability
disease MESH Cas
disease MESH CNS infections
disease MESH cancer
drug DRUGBANK Nitroglycerin
pathway REACTOME Metabolism
disease MESH hepatitis
disease MESH HIV infections
drug DRUGBANK Guanosine
disease MESH mul
disease MESH sclerosis
drug DRUGBANK Pyridoxal Phosphate
pathway KEGG Herpes simplex virus 1 infection
disease MESH Park
disease MESH dys
disease MESH genetic diseases
drug DRUGBANK Naproxen
disease MESH alternating hemiplegia
disease MESH mental disorders
drug DRUGBANK Trestolone
disease MESH brain diseases
disease MESH central nervous system disorders
disease MESH hepatocellular carcinoma
pathway KEGG Hepatocellular carcinoma
drug DRUGBANK Carboxyamidotriazole
disease MESH rare diseases

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