Host functions used by hepatitis B virus to complete its life cycle: Implications for developing host-targeting agents to treat chronic hepatitis B

Abstract

Similar to other mammalian viruses, the life cycle of hepatitis B virus (HBV) is heavily dependent upon and regulated by cellular (host) functions. These cellular functions can be generally placed in to two categories: (a) intrinsic host restriction factors and innate defenses, which must be evaded or repressed by the virus; and (b) gene products that provide functions necessary for the virus to complete its life cycle. Some of these functions may apply to all viruses, but some may be specific to HBV. In certain cases, the virus may depend upon the host function much more than does the host itself. Knowing which host functions regulate the different steps of a virus’ life cycle, can lead to new antiviral targets and help in developing novel treatment strategies, in addition to improving a fundamental understanding of viral pathogenesis. Therefore, in this review we will discuss known host factors which influence key steps of HBV life cycle, and further elucidate therapeutic interventions targeting host-HBV interactions.

Hepatitis B Virus Precore Protein p22 Inhibits Alpha Interferon Signaling by Blocking STAT Nuclear Translocation

“…Despite the dispensable role of precore in the HBV replication cycle, the observed high viremia and low immune system activation in HBeAg ϩ chronic hepatitis B patients directs attention to the role of HBeAg and/or p22 in relation to the regulation of host defense and virus persistence (7,9,20,26). Furthermore, it has been reported that HBeAg Ϫ patients respond better to standard IFN-␣ therapy than do HBeAg ϩ patients (47-51), suggesting that either HBeAg or its precursor, p22, might have an inhibitory effect that prevents the IFN therapy from working to its full potential in HBeAg-positive patients.…”

“…Upon HBV infection, the virion containing the relaxed circular DNA (rcDNA) genome is transported into the cell nucleus and converted to an episomal cccDNA, which assembles into a minichromosome and serves as a transcription template for all the viral mRNAs (8,9). Four groups of viral RNA are transcribed from cccDNA, namely, the 3.5-kb precore mRNA that encodes the precore protein, another 3.5-kb pregenomic RNA (pgRNA) that encodes the core and the polymerase, a 2.4-kb mRNA for the large (L) envelope protein, a 2.1-kb mRNA for the middle (M) and major surface (S) proteins, and a 0.7-kb mRNA for the X protein (1,2).…”

Defined host factors support HBV infection in non‐hepatic 293T cells

“…HBV entry can be mediated by heparan sulphate proteoglycan (HSPG) such as Glypican-5 (GPC5), sodium taurocholate co-transporting polypeptide (NTCP). [11][12][13][14] HBV transcription is also regulated by liver-enriched transcriptional factors such as hepatocyte nuclear factors (HNF) including HNF1, HNF3 and HNF4, CCAAT/enhancer-binding protein (C/EBP), and nuclear hormone receptors such as RXRa and PPARa. 11,[15][16][17][18] The initial step of HBV infection involves binding of the virus to a receptor on the target cell surface and initiating viral entry.…”

Difluoromethylornithine, a Decarboxylase 1 Inhibitor, Suppresses Hepatitis B Virus Replication by Reducing HBc Protein Levels

“…However, due to the side effects of interferon-alpha or drug resistance for NAs (Zoulim and Locarnini, 2009), the current therapeutic efficacy is limited. Therefore, developing new drugs that directly target either virus or host factors for an efficient CHB treatment is viral and urgent (Mitra et al, 2018).…”