Hepatitis B virus (HBV) infection remains a major cause of liver diseases and hepatocellular carcinoma. HBV infection begins by low-affinity attachment to hepatocytes and subsequent binding with a specific receptor sodium taurocholate cotransporting polypeptide (NTCP) on sinusoidal-basolateral side of liver parenchymal cells. Following internalization with an unclear mechanism, HBV undergoes uncoating, capsid disassembling and culminates in delivering its genome into the nucleus and forms the covalently closed circular (ccc) DNA. In this review, we briefly summarize the current understanding of HBV entry and discuss some unanswered questions along the entry pathway beyond NTCP binding into the nucleus.
Hepatitis B virus (HBV) infection is a major public health issue globally. It is estimated 292 million people, corresponding to 3.9% global population, are infected by the virus [1]. HBV is a small-enveloped virus with an approximately 3.2 kilobase DNA genome. Three envelope proteins—large (L), middle (M), and small (S)—are encoded in a partially overlapped ORF. However, only the PreS1 domain of the L protein (which has a myristylation modification in the N terminus) and the antigenic loop (AGL) domain of the S protein have been demonstrated essential for viral entry into host cells, and they apparently function independently [2]. The identification of NTCP as a bona fide receptor for HBV and HDV has enabled establishment of new tools for basic research and antiviral drug development against the viral infections [3••]. HDV is a small RNA virus residing in cellular nuclear. It shares the same envelop with HBV and can propagate only in the presence of HBV. HDV is believed to undergo early entry steps similar to that of HBV [4], but it is unclear whether they share the same pathway for nuclear entry. Here, we briefly summarize current understanding of HBV entry starting from cell surface receptor binding to getting into the nucleus, and pharmacological agents modulating the process.
HBV is a blood–borne virus, its infection initiates form engagement with heparan sulfate proteoglycans (HSPG) on sinusoidal-basolateral domain of plasma membrane of liver parenchymal cells [5]. HSPGs comprises multiple members from syndecan and glypican family [6]; among glypicans, GPC5 was reported to facilitate HBV attachment to the surface of hepatocytes through electrostatic interactions [7]. HSPG interacts with S domain mainly through AGL, an apparently well exposed structure stabilized by
Viral internalization usually engages a set of cellular machinery, particularly molecules in endocytic transportation. The molecular mechanism of HBV intracellular trafficking remains obscure, though some experimental observations reported clathrin-dependent, caveolae-dependent, or micropinocytosis-dependent endocytosis involved in HBV internalization [31,32]. Factors functioning after HBV-NTCP binding are expected to facilitate HBV endocytosis. A study showed that EGFR traffics with NTCP in a
The majority of hepatocytes stay in a non-dividing state under normal physiological conditions. Consequently, an incoming encapsulated HBV DNA must pass through the nuclear pore complex (NPC) to reach cell nucleus. The predominate HBV capsid form is an icosahedron construct (T = 4) with a diameter of 34 nm, comprising 120 copies of a small protein (HBc; 21 kDa) [41]. The size of HBV capsids is only slightly smaller than the NPC central opening, which is known to allow passage of molecules up to
In summary, identification of NTCP as a receptor for HBV advances our understanding of molecular mechanism of HBV infection. Productive HBV entry begins with high-affinity binding of NTCP after HSPG engagement, followed by receptor-mediated endocytosis, in which EGFR-dependent signal pathway is probably involved. HBV penetrates into the cytoplasm before transporting to the cell nucleus where cccDNA formation is established. We only start to understand this process and many basic questions are
Wenhui Li is a co-founder of Huahui Healthcare Ltd. Other authors declare no potential conflict of interest.
Papers of particular interest, published within the period of review, have been highlighted as:
The authors are supported by grants from Chinese Ministry of Science and Technology (2020YFA0707401), Beijing Municipal Commission of Science and Technology, and Tsinghua University.
