Downregulated HIPK2 Expression in T Cells Is Associated with Occult Hepatitis B Virus Infection

Occult hepatitis B virus (HBV) infection (OBI) has the same transmission routes and clinical outcomes as overt HBV infection. However, due to the lack of reliable biomarkers, its occurrence and potential clinical harm are often overlooked. We previously found that the prevalence of OBI increases with age among individuals vaccinated at birth, but the transcriptome characteristics of their immune cells remain unknown. In this study, fifteen subjects born between 1987 and 1993 and vaccinated perinatally were recruited. They were divided into OBI, inactive chronic HBsAg carriers (ICHC) and healthy control groups. Blood samples were drawn from each subject for scRNA-seq and subsequent validation studies. The results showed that eleven cell types and nine T-cell subsets were identified, with no significant differences in the proportions of T-cell subsets among the three groups. HIPK2 expression in T cells was downregulated 1.42-fold in the OBI group versus healthy controls (p = 2.01 × 10^-69) and upregulated 1.34-fold versus the ICHC infection group (p = 9.95 × 10^-61). Differentially expressed genes (DEGs) in immune-related pathways were enriched in the OBI group. TP53 plays a central role in HIPK2 function in the context of OBI. Serum HIPK2 levels were significantly lower in the OBI group than in the healthy controls (p = 0.047), but they were also significantly lower than in the ICHC infection group. In conclusion, downregulated HIPK2 expression in T cells is associated with OBI. The functional role of HIPK2 in OBI, including its role as a biomarker to distinguish OBI from a healthy status, warrants further investigation.