HBV- life cycle

3. Life cycle

1. Process
   1. EntryH1
      the 75aa at the N-terminal portion of the PreS1 domain of L-HBsAg are required residues responsible for binding to the viral receptor.[104]
      In addition, it was shown that N-myristylation of the PreS1 domain is required for infectivity, but not HBV virion assembly.[105] In fact, a myristylated peptide consisting of only the first 47 aa of the preS1 domain is able to bind to hNTCP and inhibit the binding of HBV.
      
      H11
      HBV gains entry into hepatocytes initially through a low-affinity interaction between heparan sulfate proteoglycans on the hepatocytes involving the antigenic loop (“a” determinant or antibody neutralization domain) of the HBV envelope proteins6,7 and then a high-affinity interaction of the myristoylated pre-S1 domain with the liver-specific receptor sodium/taurocholate
      cotransporter (NTCP).8 NTCP is exclusively expressed on the basolateral/sinusoidal membrane of hepatocytes. Its natural function is to transport conjugated bile salts (e.g., taurocholate) into hepatocytes as part of the enterohepatic pathway
      
      the HBV-hNTCP complex may enter the cell through clathrin-mediated endocytosis.[108] Once in the cell, the HBV DNA is delivered into the nucleus by mechanisms that remain unclear. One potential mechanism is the active transport of the nucleocapsid through nuclear pores.[109] Another potential mechanism involves CTD phosphorylation of the core protein, which is thought to expose nuclear localization signals
      H11
      The HBV genome–containing nucleocapsid is transported into the nucleus through a yet-undefined pathway, probably involving microtubule and nuclear importin machinery.16 In the nucleus, the relaxed circular, partially double-stranded genome is then repaired to a full-length, circular DNA by covalently attached viral polymerase (P) and other incompletely understood mechanisms probably involving tyrosyl DNA phosphodiesterase of the topoisomerase and DNA repair pathway. 17 The circularized protein-free genome then complexes with host histone and nonhistone proteins including various histone-modifying enzymes into a minichromosome that functions as the template for transcription.
   2. cccDNAH1
      Additionally, it has been suggested the half-life of a single cccDNA molecule is between 33 and 57 days,[132, 134] underscoring the role of cccDNA in maintaining HBV persistence.
      Transcription of viral RNA from cccDNA is lost in the absence of HBx,[28, 114] and HBx has been suggested to regulate levels of cccDNA histone acetylation and methylation.[115] Host RNA polymerase II uses cell-specific transcription factors and cccDNA, which serves as the template for all viral transcripts, to produce 5’-capped and 3’-polyadenylated RNA transcripts
      H11
      The covalently closed circular DNA (cccDNA) is transcribed to three classes of HBV RNAs: genome-length RNAs (pregenomic and precore RNAs coding for core gene products and P protein), S RNAs (S proteins), and X RNA (HBx protein).
      H10
      So far,however, dslDNA
      intermediates with these terminal redundancies have not been detected,suggesting that they are either a very short-lived inter-
      mediate or that ccc DNA is formed directly from rcDNA. CccDNA is detected in the liver within the first day of infection of
      ducklings withD HBV(Tagawaetal.,1986). CccDNA binds to histones and forms a mini-chromosome
      
      that nucleoside analogues that inhibit the RT function of polymerase do not prevent cccDNA formation,
      that cccDNA is bound to both core protein[53] and HBx
   3. Encapsidation of pgRNAH1
      
      Specifically, the 5’ end of the pgRNA contains an encapsidation signal, termed ε, which is recognized and bound by polymerase. Studies have also shown that the 5’ cap structure is required for packaging of the pgRNA;[116] however, polyadenylation is not required.
      
      This requires encapsidation of pgRNA by 120 dimers of core protein to form the nucleocapsid.
   4. reverse transcriptionH1
      Once packaged, reverse transcription is initiated through priming by the polymerase from a specific tyrosine residue within the N-terminal, TP domain of the polymerase.
      In addition, recent evidence has suggested a role for core protein in regulating DNA synthesis, as mutations in core protein inhibit the synthesis of the (+)-strand of DNA.
      
      1. step of genome replication1. polymerase binds to epsilon. this binding leads to the priming of RT from Y65 in TP domain. it is dependent on chaperones Hsp90, Hsp70, p23
         2. transfer of dna primer from epsilon to DR1 near 3 end
         3. elongation of minus strand, digestion of pgRNA
         4. transfer of primer from DR1 to DR2 to begin synthesis of plus strand
         5. pembentukan sirkularisasi genome
   5. envelopmentH1
      For example, it has been suggested that only mature rcDNA-containing nucleocapsids are enveloped, while ssDNA or RNA containing nucleocapsids are not secreted from the cell.[135] Studies utilizing an RNase H-deficient polymerase, which renders the virus unable to initiate (+)-DNA strand synthesis, have suggested that only completion of the (-)-DNA strand is required for envelopment.
      The mechanisms associated with this selectivity are unknown, although the phosphorylation state of core protein, likely influenced by the nucleic acid species inside the capsid, could be playing a role.
   6. secretion from cellH1
      Recent evidence has suggested, however, that mature HBV virions are secreted from the cell using a pathway that is dependent on proteins involved in the endosomal sorting complex required for transport (ESCRT) pathway, which forms multivesicular bodies
2. Process II
   1. Infection of Hepatocytes
   2. Regulation of
      Transcription and
      Translation
   3. Replication of
      Genomic Nucleic
      Acid
   4. Virus Assembly and Release
3. Picture
   1. 
      Link: https://www.dropbox.com/s/dr1y41135yj62ih/life%20cycle%201.jpeg?dl=0
   2. 
      Link: https://www.dropbox.com/s/jntxbsl2kbfztbo/life%20cycle%202.jpeg?dl=0
4. ProblemH1
   Although amino acid sequences of both preS1 and hNTCP that affect binding of HBV to hNTCP are known, the lack of an effective model system that mimics a robust natural infection has hampered a complete understanding of aspects of the HBV life cycle immediately following receptor-binding
5. Host