Hepatitis B virus (HBV) is a major cause of acute and chronic viral
hepatitis. In the United States, there are approximately 250,000 to
300,000 new cases of HBV infections annually, and roughly 1.25
million chronic carriers of HBV. Globally, it is estimated that 350
million individuals are chronically infected with HBV and that one
million people die annually from chronic hepatitis, liver
cirrhosis, and hepatocellular carcinoma induced by HBV. HBV belongs
to the family of Hepadnaviridae, which are small enveloped viruses,
with a partially double-stranded, relaxed-circular (RC) DNA genome.
The hepadnaviruses are classified as para-retroviruses because they
replicate this DNA genome through reverse transcription of an RNA
intermediate, the pregenomic RNA (pgRNA). In the cytoplasm of the
hepatocyte, pgRNA is selectively packaged along with the virally
encoded reverse transcriptase (RT) into HBV nucleocapsids. The
encapsidation of pgRNA requires the recognition and binding of RT
to a stem-loop structure located at the 5' end of the pgRNA called
epsilon (epsilon). The formation of the RT-epsilon
ribonucleoprotein complex triggers viral assembly and leads to the
specific incorporation of both the pgRNA and RT into
replication-competent nucleocapsids where reverse transcription
takes to form the mature RC DNA genome. For a long time, it was
thought that the adaptive and innate immune responses were
primarily responsible for providing protection against viral
pathogens. However, during mammalian evolution, a variety of
mechanisms have arisen to rid the host of viral infectious agents.
It is becoming increasingly clear that dominant inhibitory cellular
factors can also have an important role in controlling host
susceptibility. Recent studies have established that the APOBEC3
cytidine deaminases represent a major defense barrier against a
wide range of viruses. APOBEC3 is a member of the APOBEC family of
cytidine deaminases that also includes APOBEC1, -2, and the
activation induced deaminase. In humans, the APOBEC3 subfamily has
been expanded to include seven members, APOBEC3A to H, which lies
in tandem on chromosome 22. Recently, the cellular protein APOBEC3G
(A3G) was shown to inhibit the infectivity of Vif-deficient HIV-1.
A3G packaged into the viral particle mediated deamination of dC
residues in the nascent minus-strand DNA during reverse
transcription of the HIV-1 genome. As a result of this deamination,
G-to-A hypermutation of the plus-strand DNA could occur, resulting
in an increased proportion of non-infectious virus. Alternatively,
the uracil-containing DNA may prevent accumulation of reverse
transcripts, either by triggering degradation by cellular DNA
enzymes or by impairing viral protein synthesis. The known
specificity of A3G on single-stranded DNA suggested that it might
inhibit any virus with a single-stranded DNA intermediate, such as
the para-retrovirus HBV. We showed that A3G, as well as several of
the other APOBEC3 proteins, could inhibit HBV DNA replication by
acting mainly at the DNA level, with only a minor effect on viral
RNA packaging. However, inhibition of HBV DNA synthesis was not by
editing of the viral genome, but rather, the main mode of
inhibition was via a deaminase-independent mechanism. Although it
is still poorly understood, the editing-independent mechanism of
A3G seemed to target a very early stage during viral reverse
transcription to block HBV DNA synthesis. Furthermore, by using a
native agarose gel electrophoresis assay that can specifically
measure the levels of A3G incorporation into HBV nucleocapsids, we
found that A3G was specifically packaged into replication-competent
HBV nucleocapsids in a...
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