An Overview of Hepatitis B Virus Surface Antigen Secretion Inhibitors

Abstract

Current anti-hepatitis B virus (HBV) regimen do not meet ideal result due to emerging resistance strains, cytotoxicity, and unfavorable adverse effects. In chronic HBV infection, high rates of sub-viral particles (SVPs) bearing HBV surface antigen (HBsAg) is a major obstacle regarding to raise effective immune responses and subsequently virus clearance. Development of potent HBsAg secretion inhibitors would provide a better insight into HBV immunopathogenesis and therapy. Investigating new non-toxic HBsAg secretion inhibitors targeting either viral or cellular factors could restore the immune response to remove virally infected hepatocytes after inhibiting SVPs. In this study, we overview several classes of HBV inhibitors with focus on their limitations and advantages over anti-HBsAg secretion potential.

Hepatitis B subviral envelope particles use the COPII machinery for intracellular transport via selective exploitation of Sec24A and Sec23B

“…The presently available antiviral treatments for HBV infection reduce viral replication but do not affect SVP levels in the blood (Revill et al, ). In infected patients, SVPs constitute the bulk of circulating viral particles and are thought to exhaust B and T cell responses, to interfere with signaling in adaptive and innate immune function, and to contribute to viral persistence (Hu & Liu, ; Mohebbi et al, ). New approaches to treating HBV include an interference with SVP trafficking and secretion (Mohebbi et al, ).…”

“…In infected patients, SVPs constitute the bulk of circulating viral particles and are thought to exhaust B and T cell responses, to interfere with signaling in adaptive and innate immune function, and to contribute to viral persistence (Hu & Liu, ; Mohebbi et al, ). New approaches to treating HBV include an interference with SVP trafficking and secretion (Mohebbi et al, ). Candidate compounds include nucleic acid polymers (NAPs), cell‐permeable phosphorothioate oligonucleotides that had been shown to selectively inhibit SVP assembly/release in vitro and in vivo (Blanchet, Sinnathamby, Vaillant, & Labonte, ).…”

“…Besides genome‐free virions, RNA‐containing virions, naked NCs, and empty subviral envelope particles (SVPs) are produced consisting of only the viral envelope proteins (Hu & Liu, ; Prange, ). Remarkably, SVP types, also referred to as hepatitis B surface antigen (HBsAg) particles, are secreted in extreme surplus compared with the infectious HBV particles and are thought to act as decoys to the immune system, thereby exhausting B and T cell responses and contributing to viral persistence (Hu & Liu, ; Mohebbi, Lorestani, Tahamtan, Kargar, & Tabarraei, ). Confronting the host with several distinct particle types in huge amounts might also be one of the reasons for HBV's immense success as a human pathogen.…”

Modeling the dynamics of hepatitis B infection, immunity, and drug therapy

“…Current therapies control virus replication alone and only affect HBsAg levels in blood in a limited number of patients. The experimental and pharmacological field is moving toward creating better strategies for targeting HBsAg and their actions . This is opening new avenues for modelers and theoretical scientists to work alongside any new data to provide guidelines on therapy design, estimate its efficacy, or potentially explain any mechanisms that hindered its effects.…”

Hepatitis B Virus Exploits ERGIC-53 in Conjunction with COPII to Exit Cells

“…In addition to the mature virions, HBV produces and releases subviral particle types-in particular, noninfectious, spherical empty envelope subviral particles (SVPs) [26]. These particles, also referred to as hepatitis B surface antigen (HBsAg) particles, are secreted in extreme surplus compared to the infectious HBV particles and are thought to act as decoys to the immune system [26,27]. The viral S envelope protein alone is sufficient for the production of spherical SVPs with diameters of about 22 nm that are formed by self-assembly of about 100 S molecules in the ER-Golgi intermediate compartment (ERGIC) and are released via the constitutive pathway of secretion [28,29].…”