HBV

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Rough working notes, 6/2006, www.csse.monash.edu.au/~lloyd/tildeStrings/Virus/HBV/index.shtml

The Cast

  1. Virus: Its parts in the various stages of its ["life"-cycle].
  2. Liver: Hepatocytes, ~ 1012 cells [Lit05].
  3. [Immune system]:
    1. TH cells (helper T-cells).
    2. CTL cells (cytotoxic, killer T-cells).
    3. B-cells, antibodies.
  4. Drug(s), ?3TC?, lamiduvine, adefovir, entecavir.

Genome: Incomplete double-stranded DNA

m
R
N
A
NB. scale is only very approximate! 3.2K ±
        .8         1.6         2.4         3.2
  ...   +strand DNA...
  ...   - strand DNA...
  ...Pre-S2 >S>   >Pre-S1 >...
LHB 2.4k ...   *gp42 (env) ...
MHB & SHB 2.1k ... *HBsAg (gp27, env)   *gp36 (env) ...
  ...>   >P...
pre- gen 3.5k
pol & core
... *DNA-pol ...
...
YMDDV ^  
RT_204~Pol_552
RNaseH term. prot. spacer ...
  *HBcAg (core)  
    >Pre-C >C>  
pre- core 3.5k+   *HBeAg  
    >X>  
X 0.7k   HBxAg  
  .1        .8         1.6         2.4         3.2
key: * = initiation of transcription(?);
env = envelope; Ag = antigen
Long, medium and short versions (LHB, MHB, SHB) of surface protein, S, depending on start site.
Long "involved" in entering cell.
Polymerase, P, includes the reverse-transcriptase, RT.
Pol is bound to the pre-genomic RNA which it processes to DNA after packaging, then bound to the DNA until after DNA entry into cell nucleus.
Major dual reading frame overlap, S:P, means that mutations in one gene may affect the other protein.
Long Pre_C+C, and short real C. Latter makes the core (shell) of viral particle.
Pre-core accessory protein. Thought to suppress immune system response, e.g., [Wie05].
Also see [HHL00]; HBeAg -ve (pre-core -ve) => many mutations v. +ve.
NB. Core produced from pre-genomic RNA, pre-core from a separate, long(!), mRNA.
X, "accessory protein" [LL04, p.313],
multipurpose regulator, ?implicated cancer?, dampen immune sys., e.g., [Wie05].
HBV virion ~ 42nm dia..
Also see "dud" 22nm viron± particles, and misc. HBsAG* particles in serum.

Polymerase, RT

<1
(...pre-S2...)
<183 (166)
<349 (344, units=AAs) 692>
(153) 845>
terminal protein TP spacer
rt1 Pol/RT rt344
I(G) - II(F) - A
L80V/I
- B
V173L
L180Ml
A181Ta
S184Ge
- C
M204V/I/Sl


S202Ie
- D


N236Ta
M250Ve
- E
l lamiduvine, resist. 70% after 4y.; a adefovir, resist. 2% after 2y.; e entecavir (new); -- [Loc04] p.8.
RNaseH
after [Loc04] p.7, after Angus et al.

"Life"-cycle

  1. Viron in serum.
  2. Attach; get through membrane.
  3. Uncoating from the surface proteins.
  4. Genome & attached Pol. enter nucleus;
  5. Remove Pol.. Repair to ccc-DNA, covalently closed circular DNA (by cell). Form mini chromosomes.
  6. Ccc DNA transcribed to mRNA; exported from nucleus.
  7. Pre-S1 RNA -> long surface.
    Pre-S2 RNA -> medium and short surface.
    Pre-genomic RNA -> core and Pol..
    Pre-core RNA -> pre-core protein.
    X RNA -> X.
  8. Packaging of pre-genomic RNA and Pol. in core icosahedron.
  9. Pregenomic RNA (3.5K) reverse transcribed (RT) to DNA inside viral capsule.
    (i)  RNA, 3' to 5', -> DNA -ve strand (and RNA degraded).
    (ii) DNA -ve, 3' to 5' -> DNA +ve synthesised.
    The (incomplete) strands are attached to Pol..
    ? RT seems to get just one chance per viron at doing its job? ?3K (?6K) choices to make. Good target.
    ? How active, how specific, is RT during RNA -> DNA?
    "mutn rate 1.4 to 3.2×10-5 mut./site/y", [Loc04 p.6], "10× most DNA viruses" (still seems quite specific -LA).
    NB. Some capsules re-cycled into nucleus to boost ccc-DNA. (At what stage?)
  10. Envelopment of core by surface proteins after rev. transcription starts;
  11. Exit cell.

HBV infection

Hepatocyte ~ a kind of liver cell. ?What other kinds?
Acute infection
and viral clearance.
Chronic infection
TH2 cells -> antibody prodn but no viral clearance. Weak CTL response, persistent inflammation, may lead to cancer. [LL04]
?Does not remove source of production?

Immune System

Adaptive Immunity (TH, CTL, antibodies, B-cell).
Antigen Presenting Cells (APCs): A misc. collection of cells inc. dendritic, B-cells and macrophages [Alb94, p.1240]; present antigens to TH cells.
(i)  ? APC --[contact antigen & (IL1 or B7)]-> ? TH1 --[IL2 γ-interf.]-> CTL cells [LL04 p.302] [Alb94 p.1245],
CTLs recognise antigen displayed by infected hepatocytes, kill them, removing source of production.
(ii) APC --[contact antigen & (IL1 or B7)]-> TH2 --[contact match & IL4, IL5]-> B-cell which v.specifically make antibodies which bind to free particles -> "complement" proteins mop them up.
(If only 1 signal, TH inactivated, ?tolerance? [Alb94 p.1242].)
Innate Immunity?
natural killer cells (NK, NKT) attack infected hepatocytes.
Lymphocytes, 2×1012 in human body[Alb94 p.1196]
B-cells
Have receptors for free antigens.
Activated by TH cells, make antibodies (soluble form of B-cell receptors).
5×107/day in mouse [Alb94 p.1198].
T-cells
Cytotoxic (killer) T-cells (CTL)
Kill infected cells on recognition of antigen on cell's surface.
Helper T-cells TH
Receptors bind to antigens on (good) APCs.
Activates B-cells, CTLs and more TH chemically.
AKA CD4+cells or T4-cells.
An antibody is specific to an antigen; made by a B-cell clonal family, binds to matched free antigen; neutralizes antigen.
Human makes >1015 different antib. molecules [Alb94 p.1221]. ?quantity or variety?
An infected cell, displaying an antigen (12-15 AAs) on its surface, may be targetted for attack by CTLs.
APCs (good) present antigens to TH cells which signal CTLs and B-cells.

Sources

[Alb94] B. Alberts et al. The Molecular Biology of the Cell. Garland, 3rd edn 1994.
Ch.23 p.1195-1254, the immune system.
[BTC04] A. Bartholomeusz, B. G. Tehan, D. K. Chalmers. Comparisons of the HBV and HIV polymerase, and antiviral resistance mutations. Antiviral Therapy, 9, pp.149-160, 2004.
3TC -> rtM204I/V, rtL180M, p.150; (rtL80I/V or rtL82M) & rtM204I, p.153; adefovir -> rtN236T, ±rtA181V/T
[HHL00] C. Hannoun, P. Horal, M. Lindh. Long-term mutation rates in the hepatitis B virus genome. J. General Virology, 81, pp.75-83, 2000.
3 mothers, total 10 adult children, avg 26.5y HBeAg +ve
(pre-core)
chronic 9mutn(×1)
mild 0-2mutn, v.stable
HBeAg - ve severe 19,27mutn
mild 15,19,20mutn
and 108/ml "high", 105.5/ml "moderate". p.77 p.78 re pre-core (HBeAg) `stop' mutations.
p.76 & p.77, v. NCBI genomes, B: D00329 - D00331, D23678, D23679, D50521, D50522, M54923, X97851, X9807. D: J02203, L27106, M32138, U95551, X02496, Z35716, X68292, X85254, X80925.
[LL04] J. Y. Lee, S. Locarnini. Hepatitis B virus: pathogenesis, viral intermediates, and viral replication. Clin. Liver Dis., 8, pp.301-320, 2004.
lamiduvine -> rtM205I/V, rtL180M; famciclovir -> rtL180M; adefovir -> rtN236T; --p.313.
[Lit05] S. Litwin, E. Toll, A. R. Jilbert, W. S. Mason. The competing roles of virus replication and hepatocyte death rates in the emergence of drug resistant mutants: Theoretical considerations. J.Clinical Virol., 34(S1), s96-s107, 2005.
... 1012 hepatocytes... human liver.   mutn rate ~ 10-4 mut./site/year.
[Loc04] S. Locarnini. Molecular Virology of Hepatitis B Virus. Seminars in Liver Dis., 24 (S1), pp.3-10, 2004.
mutn rate 1.4 to 3.2×10-5 mut./site/y., load can be ~ 1011virions/ml, half-life in serum ~ 1-2 d, production ~ 1011v/d,
[Wie05] S. F. Wieland & F. V. Chisari. Stealth and Cunning: Hepatitis B and Hepatitis C Viruses. J.Virology, 79(15), pp.9369-9380, Aug. 2005
HBeAg has been shown to suppress the antibody & T-cell response... (HBsAg) might also suppress immune elimination of infected cells... HBx protein has the potential to inhibit antigen processing... as many as 10**11 hepatocytes can be infected
Wikipedia [2006], [Liver], [Hepatocyte], [Hepatitis], [HBV], [immune-system],
Liver 1.3-3.0kg, "Hepatocytes make up 60-80% of the cytoplasmic mass of the liver", ">95% of people who become infected as adults or older children will stage a full recovery", "[HBV] one of a few known non-retroviral viruses which employ reverse transcription".
Also see [Bibliography].
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© L. Allison   http://www.allisons.org/ll/   (or as otherwise indicated),
Faculty of Information Technology (Clayton), Monash University, Australia 3800 (6/'05 was School of Computer Science and Software Engineering, Fac. Info. Tech., Monash University,
was Department of Computer Science, Fac. Comp. & Info. Tech., '89 was Department of Computer Science, Fac. Sci., '68-'71 was Department of Information Science, Fac. Sci.)
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