Molecular mechanisms underlying occult hepatitis B virus infection

Abstract

Chronic hepatitis B virus (HBV) infection is a complex clinical entity frequently associated with cirrhosis and hepatocellular carcinoma (HCC). The persistence of HBV genomes in the absence of detectable surface antigenemia is termed occult HBV infection. Mutations in the surface gene rendering HBsAg undetectable by commercial assays and inhibition of HBV by suppression of viral replication and viral proteins represent two fundamentally different mechanisms that lead to occult HBV infections. The molecular mechanisms underlying occult HBV infections, including recently identified mechanisms associated with the suppression of HBV replication and inhibition of HBV proteins, are reviewed in detail. The availability of highly sensitive molecular methods has led to increased detection of occult HBV infections in various clinical settings. The clinical relevance of occult HBV infection and the utility of appropriate diagnostic methods to detect occult HBV infection are discussed. The need for specific guidelines on the diagnosis and management of occult HBV infection is being increasingly recognized; the aspects of mechanistic studies that warrant further investigation are discussed in the final section.

Fig 1

Overview of mechanisms leading to occult hepatitis B virus (HBV) infection.

Fig 2

HCV coinfection in occult HBV infection. HCV core protein inhibits HBV gene expression by directly interacting with HBx protein and suppresses HBV replication by interfering with the binding of core and polymerase to package signal “ε” present in pregenomic RNA (pgRNA) within the hepatocyte, thereby preventing HBV encapsidation.

Fig 3

Role of APOBEC deaminases in occult HBV infection. (A) Deamination activity of APOBEC protein converts cytosine to uracil in the HBV genome, leading to various mutations associated with occult HBV infection. (B) Deamination-independent activity of APOBEC deaminases inhibits DNA-RNA hybrid formation, increases susceptibility to nuclease digestion, and decreases protein processing, eventually leading to occult HBV.

Fig 4

Host immunological responses leading to occult HBV infection. Host-derived responses, including a noncytolytic T-cell response, VDR polymorphism, immunosuppression, and differential regulation of apoptosis, contribute to the etiopathogenesis of occult HBV infection.

Fig 5

Mechanism of occult HBV infection via methylation of HBV DNA. HBV induces expression of cellular DNA methyltransferases (DNMTs), leading to methylation of CpG dinucleotides in the HBV genome. Hypermethylation impairs HBV replication, virion production, and HBV protein levels, leading to occult HBV infection.