Complete HBV Genome Analysis in HIV Coinfected Individuals Identifies a Novel Core/precore Mutant 

Liver failure has emerged as a major cause of morbidity and mortality in HIV positive people coinfected with hepatitis B virus (HBV). Increased HBV replication in HIV-HBV coinfected individuals as compared with HBV monoinfected individuals suggests that the HBV genome may differ in coinfected individuals, according to the authors of a study presented last week at the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention last week in Sydney, Australia.

In HBV monoinfected individuals on immunosuppressive therapy, core deletion mutants are associated with more aggressive liver disease. Since HIV accelerates HBV liver disease progression, the investigators hypothesized that HIV-HBV coinfected individuals may have increased frequency of core mutations.

To test this hypothesis, they analyzed genome-length sequences of HBV DNA from HIV-HBV coinfected individuals. Genomic length HBV DNA was amplified by PCR from serum samples from 98 coinfected subjects. The complete HBV genomes were then sequenced and analyzed. The frequency of particular mutations in the HBV core gene was determined by cloning virus from a subset of 10 individuals. To determine the replication phenotype of viruses harboring this mutation, the mutation was introduced into infectious HBV cDNA and transfected into hepatoma cells in the laboratory. The replication phenotype of the mutant virus was determined by measuring HBV DNA, RNA, and protein.

Results

• The researchers identified a novel HBV mutant with a single frame-shift mutation in the overlapping HBV precore/core genes.

• This mutation was in an immunodominant CD4 epitope.

• Cloning showed that the mutant genome was the dominant species in some patients, although wild-type HBV was always detected in association.

• In vitro analysis showed that the mutant was incapable of autonomous replication and replication was rescued by co-expression of the HBV core protein.

• The phenotype of the mutant virus in vitro was HBeAg-negative.

Conclusion

In conclusion, the investigators wrote, "The emergence of HBV harboring a novel mutation in an immunodominant region of the core gene may be one explanation for the higher levels of HBV replication observed in HIV/HBV coinfected individuals."

VIDRL, North Melbourne, Australia; VIDS, Melbourne, Australia; Alfred Hospital, Melbourne, Australia; National Center for HIV Epidemiology and Clinical Research, Sydney, Australia; Johns Hopkins University, Baltimore, MD.

Hepadnaviruses have the among the smallest genomes of all known viruses, consisting of two uneven strands of DNA: (-) sense strand: 3.0 - 3.3kb (size varies between different Hepadnaviruses) (+) sense strand: 1.7 - 2.8kb (size varies between different particles)

08/03/07

Reference
P Revill, M Littlejohn, A Ayres, and others. Complete HBV genome analysis in HIV coinfected individuals identifies a novel core/precore mutant. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Sydney, Australia, July 22-25, 2007. Abstract TUPDA06.