Occult hepatitis B infection
Teresa Pollicino email
,
Giovanni Raimondo email
Received: January 12, 2014; Received in revised form: April 21, 2014; Accepted: April 24, 2014; Published Online: June 26, 2014
DOI: http://dx.doi.org/10.1016/j.jhep.2014.04.036
Keywords:
Occult HBV infection, Immunological control of HBV, Epigenetic control of HBV, Clinical implication of occult HBV infection
Occult hepatitis B virus (HBV) infection (OBI) is recognized as one of the possible phases in the natural history of chronic HBV infection [1]. OBI defines the persistence of HBV genomes in the hepatocytes of individuals testing negative for HBV surface antigen (HBsAg) and, usually, also for serum HBV DNA [2]. Apart from some cases in which the lack of HBsAg detection is attributable to the HBV genetic heterogeneity (i.e., infection with replication-defective variants or with S-escape mutants producing a modified HBsAg undetectable by diagnostic kits), in most cases OBI is related to replication-competent viruses that are strongly suppressed in their activities (replicative and transcriptional) by the host’s defense mechanisms. Very importantly, this suppression (a) does not have an absolute effect and residual, low-levels of replication and transcription may persist over time, and (b) may be reversible in particular circumstances leading to viral reactivation and development of a typical HBsAg-positive (namely, “overt”) infection [[3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14]].
Schematic comparison of overt and occult HBV infection. Mechanisms potentially involved in HBV inhibition and OBI induction are summarized. In particular, immunological (presence of functionally efficient central/effector memory T cells), genetic (HBV genomic variability, APOBEC hyperediting), epigenetic (methylation of CpG-rich regions within the HBV genome as well as acetylation/methylation of cccDNA-bound histones and recruitment of chromatin modifying enzymes onto the viral minichromosome) and co-/posttranscriptional (HBV RNA splicing, HBV replication inhibition by cellular miRNAs and by editing-independent functions of the cellular APOBEC3 proteins) mechanisms are represented. Differences in nucleosomal packaging and transcriptional activity of HBV minichromosomes as well as in amounts of total viral DNA, transcripts, proteins and virion formation and secretion are also displayed. DC, Dendritic Cell; CD4, CD4+ T cell; CD8, CD8+ T cell; RC DNA, Relaxed Circular DNA; cccDNA, covalently closed circular DNA; pgRNA, pregenomic RNA; HBs, envelope proteins; SVPs, subviral particles; TF, cellular transcription factors; HATs, histone acetyl transferases; HMT, histone methyltransferases; APOBEC3, apo B mRNA editing enzyme catalytic polypeptide; hnRNP K, heterogeneous nuclear ribonucleoprotein K; miRNAs, microRNAs; CpG meth, methylated CpG islands.