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The absence of specific antiviral treatments and licenced human vaccines underscores the importance of understanding WNV pathogenesis, particularly the mechanisms by which it evades host immune responses. This review comprehensively analyzes the multifaceted immune evasion strategies employed by WNV, encompassing the suppression of interferon (IFN) production and signalling through targeting of STAT proteins, IRF3, and RNA sensors, the modulation of antigen presentation via downregulation of MHC molecules and impairment of proteasome function, and the manipulation of cytokine and chemokine responses to dysregulate inflammation and promote viral persistence. Furthermore, WNV exploits the blood\u2013brain barrier (BBB) to gain access to the central nervous system (CNS), both by disrupting the barrier integrity and utilising \u201cTrojan horse\u201d mechanisms. The potential for antibody\u2010dependent enhancement (ADE) further complicates the host\u2010virus interaction. Understanding these immune evasion mechanisms is crucial for deciphering WNV pathogenesis and informing the development of effective vaccines and targeted immunotherapies aimed at preventing and treating WNV\u2010related diseases. Future research should focus on translating this knowledge into tangible clinical benefits for at\u2010risk populations, particularly regarding strategies to induce broadly neutralising antibody responses and robust T\u2010cell immunity while mitigating the risk of ADE.<\/jats:p>","DOI":"10.1002\/rmv.70042","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T01:55:06Z","timestamp":1748397306000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Mechanisms of Immune Evasion of West Nile Virus"],"prefix":"10.1002","volume":"35","author":[{"given":"Abdullah","family":"Alghamdi","sequence":"first","affiliation":[{"name":"Department of Medical Laboratory College of Applied Medical Sciences Prince Sattam Bin Abdulaziz University  Al\u2010Kharj Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4045-0810","authenticated-orcid":false,"given":"Mohammed","family":"Alissa","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory College of Applied Medical Sciences Prince Sattam Bin Abdulaziz University  Al\u2010Kharj Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed A.","family":"Alshehri","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory College of Applied Medical Sciences Prince Sattam Bin Abdulaziz University  Al\u2010Kharj Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"crossref","unstructured":"M. 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