Nyoman Cahyadi Tri Setiawan, Rozikin Rozikin

The Role of NS1 Gene Mutations in Dengue Virus Serotype 2 and Their Association with Clinical Severity of Dengue Hemorrhagic Fever: A Systematic Review

Introduction

The role of ns1 gene mutations in dengue virus serotype 2 and their association with clinical severity of dengue hemorrhagic fever: a systematic review . Explore the role of DENV-2 NS1 gene mutations in Dengue Hemorrhagic Fever clinical severity. This systematic review reveals how mutations like T164S impact disease progression.

Abstract

NS1 gene of Dengue Virus Serotype 2 (DENV-2) plays a significant role in the pathogenesis and clinical severity of dengue infections, including Dengue Hemorrhagic Fever. Mutations in the NS1 gene of DENV-2 are closely associated with the clinical severity of dengue. Methods: This review article employs a systematic review methodology, utilizing Scopus, PubMed and Web of Science from 2015 to 2025. Results: The T164S mutation was consistently associated with increased severity through elevated secreted NS1 (sNS1) production, complement activation, and inflammation. Conversely, the S103T mutation appeared in milder cases. NS1 mutations also correlated with immune hyperactivation, vascular leakage, and, in some cases, neurological symptoms such as encephalitis. Despite these findings, direct causality between specific mutations and clinical outcomes requires further investigation. Conclusion: Mutations in the NS1 gene of DENV-2 affect the stability, secretion, and immunogenic properties of the NS1 protein, leading to increased vascular leakage and severe disease outcomes

Review

This systematic review thoroughly investigates the significant role of NS1 gene mutations in Dengue Virus Serotype 2 (DENV-2) and their association with the clinical severity of Dengue Hemorrhagic Fever (DHF). Addressing a critical area within dengue pathogenesis, the study effectively synthesizes existing literature to elucidate how specific genetic variations within the NS1 gene contribute to adverse disease outcomes. The chosen systematic review methodology, encompassing Scopus, PubMed, and Web of Science over a recent ten-year period (2015-2025), provides a robust framework for evidence aggregation. The review's findings are compelling, pinpointing specific mutations with differential impacts on clinical severity. Notably, the T164S mutation consistently emerges as a key player in increased severity, correlating with elevated secreted NS1 (sNS1) production, heightened complement activation, and exacerbated inflammation. In contrast, the S103T mutation was associated with milder dengue cases, suggesting a protective or less pathogenic role. Beyond these specific mutations, the review broadens its scope to link NS1 mutations more generally with immune hyperactivation, increased vascular leakage, and even severe neurological symptoms such as encephalitis, thereby consolidating diverse aspects of severe dengue pathology under the umbrella of NS1 genetic variation. Despite the strong correlations identified, the authors commendably acknowledge a crucial limitation: the need for further investigation to establish direct causality between specific mutations and clinical outcomes. This caveat highlights a critical gap that functional studies will need to address. Nevertheless, the review effectively concludes that DENV-2 NS1 gene mutations profoundly impact the protein's stability, secretion, and immunogenic properties, ultimately driving increased vascular leakage and severe disease. This work provides a valuable synthesis of current knowledge, serving as an excellent foundation for future research aimed at understanding the precise mechanisms and potentially developing novel prognostic markers or therapeutic targets for severe dengue.

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