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Cao Cancer Evo-Dev

sequences) of HBV subgenotypes B2 and C2, based on HBV acquired during infancy or early childhood, or at
the whole HBV genome sequenced using approximately early infection stage in adults, is usually in the form
1,000 asymptomatic HBsAg carriers from community- of wild-type [12,38] . In the initial immune tolerant phase
based epidemiological surveys in the Yangtze river of chronic HBV infection, HBeAg is positive, viral
delta region of mainland China. Based on the wild-type load is high, and immune pressure is weak. With the
HBV sequences, we subsequently characterized the progression of chronic infection, especially during
end-stage liver diseases-related mutations and their HBeAg seroconversion, the proportion of HBV mutants
development patterns in HBV subgenotypes B2 and C2. gradually increases [40] . Although the HBV strains
We found that the HBV mutations posing a significant carrying the HCC-related mutations are present in
risk of HCC or liver cirrhosis were mainly located within the cord blood of infants, neonatal infection is usually
the enhancer II/basal core promoter/precore (EnhII/ caused by wild-type HBV strain rather than the mutant
BCP/PreC) and preS regions of HBV genome [29-31] . ones. In the HBV-infected children, the frequencies
We summarized the data concerning the association and locations of HCC-related mutations increase
of the HBV mutations and HCC risk published up to with increasing age. However, compared with their
2009, and found that the frequencies and locations of mothers who have been exposed to chronic infection
the HBV mutations accumulate consecutively during for approximately 25 years, children have fewer HCC-
the “trilogy” of HBV-induced carcinogenesis (CHB, liver related HBV mutations [38] . In individuals with chronic
cirrhosis, and HCC) and that these HBV mutations can HBV infection, HBV is synthesized and packaged in
be applied to predict the occurrence of liver cirrhosis hepatocytes and released into the circulation at a pace
and HCC [32] . In our prospective cohort study, we have of up to 1011 viral particles daily. HBV is regularly cleared
identified the baseline HBV mutations (C1653T, A1762T/ from the circulation by the host immune system, with a
G1764A, and T1753V) increase the risk of HCC both half-life of approximately 1.2 days. Thus, hepatocytes
independently and “dose-dependently”. The so-called and their surrounding immune cells are responsible
“dose-dependently” is referred to that the HCC risk is for the generation of HBV mutants [41] . HBV reverse
significantly higher in the CHB patients carrying one of transcriptase lacks proofreading activity, resulting in
the three mutations than in those without the mutation, an estimated mutation rate of 4.57 × 10 nucleotide
5
is significantly higher in those with two of the three substitutions per site per year and this rate will increase
mutation than in those with one of the three mutation, after HBeAg seroconversion [42] . Inflammatory factors
and is also significantly higher in those with all the three in the microenvironment of inflammatory liver promote
mutation than in those with two of the three mutations. the generation of HBV mutations, at least partially, via
Thus, the baseline HBV mutations in combination are activating the human apolipoprotein B mRNA-editing
able to predict the occurrence of HCC in CHB patients [33] . enzyme catalytic polypeptide (APOBEC) family of
Several longitudinal studies carried in China have also cytidine deaminases [43,44] . Although many HBV genome
demonstrated that baseline A1762T/G1764A mutation fragments including the PreC/BCP/EnhII region and the
increases the risk of HCC in chronic HBV carriers or CHB S region are generally sensitive to editing by members
patients [34-37] . Among the HCC-risk HBV mutations, the of APOBEC3, the sequence encoding HBV X protein
A1762T/G1764A is usually detected in the early stage (HBx) is more vulnerable. APOBEC3 prefers the HBx
in young adolescents, while other mutations including region as its editing target and generates carboxylic
T1753V, C1653T, G1899A, and preS deletion appear acid-terminal truncated HBx (Ct-HBx) [44] , the main form
only at the late stage of chronic HBV infection [12,38] . of HBV DNA integrated into the host genome. Insufficient
Reaction to chronic HBV infection, as characterized by immune responses elicited by HBV antigens select
immune response-induced hepatocyte damage and disease-related HBV mutations during the long-term
release of transaminase, facilitates the generation of infection process. Only the HBV variants best adapted
the HBV mutations, indicating active immune selection to the host immune system will survive and thrive in
of the HBV mutants during HBeAg seroconversion from liver. HBV accumulates mutations via minimizing the
HBeAg-positive to HBeAg-negative. One of the main total number of epitopes recognized by CD8 T cells,
+
features of HBV mutations is a deficiency of the CD8 particularly in the HBx and the preS1/preS2/S regions,
+
T-cell epitope, a consequence of immune selection. to avoid immune clearance [39] . These HBV mutations
Reduction of CD8 T cell epitopes of HBV is one of are probably selected via virus-immune interactions
+
the common strategies to evade immune eradication. in the inflammatory microenvironment. Because of
HBV that has a low density of CD8 T cell epitope in overlapping open reading frames, HBV mutations
+
their core and X proteins are selected during long-term altering the genes necessary for viral replication are
evolution [39] , thus CD8 T cells play an important role unlikely transferred into their progeny viruses. Natural
+
in the immune selection of HCC-related HBV mutants selection ensures only the fittest survive to pass their
[Figure 2]. genes on to the next generation. Thus, the random
244 Hepatoma Research ¦ Volume 3 ¦ October 27, 2017