Ebola Virus Persistence in Immune-Privileged Niches: Molecular Mechanisms, Host-Virus Interactions, and Therapeutic...

Ebola virus disease (EVD) has traditionally been conceptualized as an acute, fulminant illness culminating in either death or apparent systemic viral clearance. However, clinical, virological, and genomic evidence gathered since the 2013-2016 West African epidemic demonstrates that Ebola virus (EBOV) can persist for months to years within immunologically privileged anatomical compartments, particularly the central nervous system, eye, and male reproductive tract, after blood viremia becomes undetectable. Importantly, the strength of evidence differs by endpoint: RT-PCR positivity demonstrates persistence of viral RNA, recovery in culture demonstrates replication-competent virus, and documented transmission requires epidemiological and, where available, genomic linkage. Persistent infection has been associated with clinically important outcomes, including relapsing meningoencephalitis, genomically supported sexual transmission long after recovery, and outbreak resurgence linked to persistent human viral lineages. Synthesizing evidence across human cohort studies, case reports, non-human primate models, and organoid systems, this review examines the anatomical, molecular, and immunological factors that may permit EBOV survival in privileged niches. Structural barriers and local immunoregulatory environments are established features of these compartments, whereas the contributions of defective viral genomes, cell-type-specific interferon responses, exosome- or cell-mediated spread, host immunogenetic variation, and acute-phase treatment to long-term reservoir establishment remain supported to differing degrees and, in several cases, are still mechanistic hypotheses. Although monoclonal antibodies and direct-acting antivirals have transformed acute-phase outcomes, their effects on established tissue reservoirs remain incompletely defined. key knowledge gaps establishing the relationship between viral RNA detection and true infectivity, defining correlates of protection against relapse, and determining how acute-phase therapeutic choice influences reservoir establishment remains essential for developing compartment-penetrant treatments, updating survivor care guidelines, and preventing future outbreak resurgences.