Evolutionary and functional landscape of HBx mutations in genotype D1 HBV: comparative insights from acute infection, chronic hepatitis, and HCC.
8 affiliations
- 1Department of Microbiology and Medical Virology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran. [email protected].
- 2Department of Restorative and Esthetic Dentistry, Faculty of Dentistry, IQ. The Islamic University, Najaf, Iraq.
- 3Department of Surgeon Disease, Termez University of Economics and Service, Termez, Uzbekistan.
- 4Vice-Rector for Finance and Economic Affairs, Samarkand State Medical University, Samarkand, Uzbekistan.
- 5Department of Clinical Sciences, Urgench RANCH Technology University, Urgench, Uzbekistan.
- 6Department of Microbiology, Public Health, Hygiene and Management, Faculty of Pediatrics, University of Termez Branch of Tashkent State Medical University, Tashkent, Uzbekistan.
- 7Department of Professional Education, Faculty of Hydromelioration, TIIAME National Research University, Tashkent, Uzbekistan.
- 8Department of Internal Medicine in Family Medicine, Tashkent State Medical University, Tashkent, Uzbekistan.
Abstract
HBV infection remains a major global health burden and a leading cause of hepatocellular carcinoma (HCC), with viral genetic variability contributing to the heterogeneity of clinical outcomes. Among HBV proteins, HBx functions as a multifunctional regulatory protein involved in viral replication, host transcriptional regulation, apoptosis, immune signaling, and oncogenic pathways. Although HBx biology has been extensively investigated, most mechanistic insights are derived from genotype B and C infections, while genotype D-particularly subgenotype D1-remains comparatively underrepresented. This narrative review provides an integrative synthesis of reported HBx mutational patterns across distinct clinical contexts of HBV infection, including acute infection, chronic hepatitis B, and HBV-related HCC, with particular emphasis on genotype D1-dominant populations from the Middle East. The review incorporates findings from previously published phase-specific studies together with relevant external literature to explore how HBx variability may relate to functional domains and disease-associated molecular patterns. Mutations are discussed in the context of major HBx functional regions, including the N-terminal regulatory region, the transactivation domain, the H-box/DDB1-binding motif, and the BH3-like region. Structural modeling, protein-protein interaction network analysis, and phylogenetic contextualization are used as conceptual and illustrative frameworks to interpret reported variants without inferring direct causality. Reported HBx variability appears to preferentially involve structurally flexible and interaction-rich regions. Recurrent substitutions, particularly involving glycine residues, are more frequently reported in acute and chronic infection settings, whereas HCC-associated variants more commonly involve C-terminal alterations and truncation events. Collectively, these observations support a hypothesis-generating framework in which HBx functional plasticity may reflect adaptive virus-host interactions under selective pressures rather than a linear oncogenic mechanism driven by individual mutations alone. Importantly, no new experimental or clinical data are presented, and all interpretations are derived from previously published studies and in silico analyses. By emphasizing genotype D1-specific evolutionary characteristics and addressing a geographical gap in HBV research, this review may provide a useful conceptual basis for future functional investigations, genotype-stratified analyses, and translational studies in HBV-associated liver disease.
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BibTeX
@article{jalali2026evolutionary,
title = {{Evolutionary and functional landscape of HBx mutations in genotype D1 HBV: comparative insights from acute infection, chronic hepatitis, and HCC.}},
author = {Kamyar Mazloum Jalali and Ali Sameer Alkhawaja and Ilyos Xursandov and Elmurodov Gayratjon and Fotima Axmedova and Turabaeva Zarina and Ernazarova Vazira and Turakulov Rustam},
journal = {Infectious agents and cancer},
year = {2026},
month = aug,
doi = {10.1186/s13027-026-00789-w},
url = {https://europepmc.org/article/MED/43010014},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Evolutionary and functional landscape of HBx mutations in genotype D1 HBV: comparative insights from acute infection, chronic hepatitis, and HCC.
AU - Kamyar Mazloum Jalali
AU - Ali Sameer Alkhawaja
AU - Ilyos Xursandov
AU - Elmurodov Gayratjon
AU - Fotima Axmedova
AU - Turabaeva Zarina
AU - Ernazarova Vazira
AU - Turakulov Rustam
PY - 2026
DA - 2026/08/13
JO - Infectious agents and cancer
DO - 10.1186/s13027-026-00789-w
UR - https://europepmc.org/article/MED/43010014
AB - HBV infection remains a major global health burden and a leading cause of hepatocellular carcinoma (HCC), with viral genetic variability contributing to the heterogeneity of clinical outcomes. Among HBV proteins, HBx functions as a multifunctional regulatory protein involved in viral replication, host transcriptional regulation, apoptosis, immune signaling, and oncogenic pathways. Although HBx biology has been extensively investigated, most mechanistic insights are derived from genotype B and C infections, while genotype D-particularly subgenotype D1-remains comparatively underrepresented. This narrative review provides an integrative synthesis of reported HBx mutational patterns across distinct clinical contexts of HBV infection, including acute infection, chronic hepatitis B, and HBV-related HCC, with particular emphasis on genotype D1-dominant populations from the Middle East. The review incorporates findings from previously published phase-specific studies together with relevant external literature to explore how HBx variability may relate to functional domains and disease-associated molecular patterns. Mutations are discussed in the context of major HBx functional regions, including the N-terminal regulatory region, the transactivation domain, the H-box/DDB1-binding motif, and the BH3-like region. Structural modeling, protein-protein interaction network analysis, and phylogenetic contextualization are used as conceptual and illustrative frameworks to interpret reported variants without inferring direct causality. Reported HBx variability appears to preferentially involve structurally flexible and interaction-rich regions. Recurrent substitutions, particularly involving glycine residues, are more frequently reported in acute and chronic infection settings, whereas HCC-associated variants more commonly involve C-terminal alterations and truncation events. Collectively, these observations support a hypothesis-generating framework in which HBx functional plasticity may reflect adaptive virus-host interactions under selective pressures rather than a linear oncogenic mechanism driven by individual mutations alone. Importantly, no new experimental or clinical data are presented, and all interpretations are derived from previously published studies and in silico analyses. By emphasizing genotype D1-specific evolutionary characteristics and addressing a geographical gap in HBV research, this review may provide a useful conceptual basis for future functional investigations, genotype-stratified analyses, and translational studies in HBV-associated liver disease.
SN - 1750-9378
ER -