Abstract
Hepatitis B virus (HBV) DNA is vulnerable to editing by human cytidine deaminases of the APOBEC3 (A3A-H) family albeit to much lower levels than HIV cDNA. We have analyzed and compared HBV editing by all seven enzymes in a quail cell line that does not produce any endogenous DNA cytidine deaminase activity. Using 3DPCR it was possible to show that all but A3DE were able to deaminate HBV DNA at levels from 10−2 to 10−5 in vitro, with A3A proving to be the most efficient editor. The amino terminal domain of A3G alone was completely devoid of deaminase activity to within the sensitivity of 3DPCR (∼10−4 to 10−5). Detailed analysis of the dinucleotide editing context showed that only A3G and A3H have strong preferences, notably CpC and TpC. A phylogenic analysis of A3 exons revealed that A3G is in fact a chimera with the first two exons being derived from the A3F gene. This might allow co-expression of the two genes that are able to restrict HIV-1Δvif efficiently.
Highlights
The human APOBEC3 locus on chromosome 22q13.1 encodes at least seven genes encoding cytidine deaminases with single stranded DNA substrate specificity [1]
Hepatitis B virus (HBV) editing by monodomain A3A and A3H 3DPCR is so sensitive that it can amplify heavily APOBEC3 edited HIVDvif genomes even from a permissive cell line such as 293T [40]
It was presumed that this resulted from clonal heterogeneity whereby a small fraction of cells are expressing high levels of A3F/G. This phenomenon has been encountered for some other cell lines, such as Huh7. To overcome this problem we screened a number of avian cell lines because the avian genome does not encode APOBEC1 or APOBEC3 homologues [43]
Summary
The human APOBEC3 locus on chromosome 22q13.1 encodes at least seven genes encoding cytidine deaminases with single stranded DNA substrate specificity [1]. While their precise cellular roles remain to be defined, human APOBEC3F and 3G (A3F and A3G) are so active on nascent lentiviral cDNA that these retroviruses have evolved a discrete gene product, the Vif protein, to counter their otherwise devastating effects [2,3,4,5,6,7,8,9]. Pig, cattle, cat, dog and horse genomes there are from 1 to 6 APOBEC3 homologues, some of which can be coupled by intergenic splicing [22,23,24]
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