Suppression of complement component 2 expression by hepatitis B virus contributes to the viral persistence in chronic hepatitis B patients

: Previously, we identified rare missense mutations of complement component 2 (C2) to be associated with chronic hepatitis B (CHB) by exome sequencing. However, up to now, little is known about the role of C2 in CHB. In the present study, we aimed to perform preliminary exploration about the underlying role of C2 in CHB. Serum samples from 113 CHB patients and 30 healthy controls, and liver biopsysamples from 5 CHB patients and 3 healthy controls were obtainedfrom the Third Affiliated Hospital of Sun Yat-sen University between January 2018 and January 2020.HepG2.2.15 and HepG2-NTCP cells infected with HBV were used to examine the influence of HBV infection on C2 expression. IFN treated HepG2.2.15 cells were used to assess the effect of IFN on C2 expression. C2-overexpressing or C2-silencing in HepG2.2.15 cells were constructed to evaluate the effect of C2 on HBV infection. Western blot and RT-qPCR were used to measure C2 expressioninbiopsy samples. HBeAg and HBsAgin culture medium and C2 of serum samples were measured by ELISA. HBV-DNA was measured by RT-qPCR. GSE84044, GSE54747 and GSE27555 were downloaded from GEO.C2 expression inliver tissue and serum were significantly lower in CHB patients compared to healthy controls, and significantly higher C2 expression was found in CHB patients with lower ALT, AST, Scheuer grade and stages compared to CHB patients with higher ALT, AST, Scheuer grades and Scheuer stage. Besides, HBV infection could decrease C2 expression by increasing expression of Sp1 and reducing expression of HDAC4. Moreover, C2 could enhance the anti-virus effect of IFN on HepG2.2.15 cellsand also inhibit HBV replication in HepG2.2.15 cellsby inhibition of p38-MAPK signaling pathway. In conclusion, HBV may promote viral persistence in CHB patients by inhibiting C2 expression.