IDENTIFYING NOVEL HOST SUSCEPTIBILITY FACTORS FOR HEPATITIS B VIRUS INFECTION

Abstract

Even though much work has been done to understand HBV pathogenesis, how the virus manipulates host cell machinery remains underexplored. Therefore, the current study aimed to identify novel host factors affecting HBV replication. Employing whole transcriptomic sequencing analysis of HBV-infected primary human hepatocytes followed by reverse genetics, this study identified cyclin L1 as HBV host factor. The functional relevance of cyclin L1 during HBV infection has been validated in the current study using several lines of evidence: 1) knockdown of CCNL1 resulted in a remarkable reduction in HBV replication in different cell lines and in PHH, 2) knockdown of CCNL1 resulted in reduced production of HBV RNA as well as phosphorylation of total RNAPII at ser 2 which is required for viral transcription, 3) Loss-of-function of cyclin L1 resulted in reduced ccc-DNA-based transcription as supported by the low levels of cccDNA bound to RNAPII and H3K27ac; an active marker of transcription and lastly, 4) CCNL1 expression was enhanced in chronic HBV patients, highlighting its putative role in CHB infection. In summary, this study uncovers CCNL1 as an essential host factor regulating HBV replication and contributes toward understanding of complex virus: host factor interactions.