%0 Journal Article
%T The HBV S Gene C138R Mutation Induces Occult Infection through Defective HBsAg Antigenicity and Secretion
%A Mohamed Ibrahim Hassan
%A Ahmed Youssef Nabil
%J Journal of Medical Sciences and Interdisciplinary Research
%@ 3108-4826
%D 2022
%V 2
%N 1
%R 10.51847/aBB6TXFeEH
%P 85-98
%X Occult hepatitis B virus infection (OBI) is associated with substantial risks of transmission and disease progression. Alterations in the S gene are regarded as key factors in the emergence of OBI. A prior investigation by our group detected the C138R substitution in the S gene among individuals with OBI. The present work sought to examine the influence of the C138R substitution on HBsAg functionality and the underlying processes responsible for OBI. Complete HBV genome constructs (HBV 1.3, genotype B) and corresponding mutant constructs (HBV C138R) were generated, together with HA-tagged expression vectors for wild-type (sWT) and mutant (sC138R) S proteins. The consequences of the C138R substitution on HBsAg antigenicity, secretion, and dimerization were assessed via transfection experiments in cultured cells and hydrodynamic tail vein delivery in mice. The C138R substitution dramatically lowered both intracellular and extracellular HBsAg concentrations while leaving HBV transcription, replication, and expression of other viral proteins unaffected. Experiments using HA tagging showed that the decline stemmed from reduced antigenicity. Data from multiple commercial ELISA assays and HA detection in culture media indicated that the C138R substitution additionally hindered HBsAg secretion. The C107R substitution likewise substantially diminished both antigenicity and secretion of HBsAg. Non-reducing Western blot analysis combined with AlphaFold 3 structural modeling demonstrated that the C138R substitution promoted the assembly of atypical HBsAg dimers. These observations were corroborated in the murine HBV model.The C138R substitution promotes OBI by concurrently compromising HBsAg antigenicity and secretion. The main mechanism involves breakage of the disulfide bridge between residues 107 and 138, leading to the generation of conformationally aberrant dimers that impair HBsAg function.
%U https://smerpub.com/article/the-hbv-s-gene-c138r-mutation-induces-occult-infection-through-defective-hbsag-antigenicity-and-secr-cyfwaxvpi7ett5y