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

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.