Characterization of hepatitis B virus X gene quasispecies complexity in mono-infection and hepatitis delta virus superinfection
Godoy, Cristina (Hospital Universitari Vall d'Hebron)
Tabernero, David (Hospital Universitari Vall d'Hebron)
Sopena, Sara (Hospital Universitari Vall d'Hebron)
Gregori i Font, Josep (Roche Diagnostics SL)
Cortese, Maria Francesca (Hospital Universitari Vall d'Hebron)
González, Carolina (Hospital Universitari Vall d'Hebron)
Casillas, Rosario (Hospital Universitari Vall d'Hebron)
Yll, Marçal (Hospital Universitari Vall d'Hebron)
Rando-Segura, Ariadna (Hospital Universitari Vall d'Hebron)
Lopez Martinez, Rosa (Hospital Universitari Vall d'Hebron)
Quer, Josep 1963- (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
González-Aseguinolaza, Gloria (Clínica Universidad de Navarra. Centro de Investigación Médica Aplicada)
Esteban, Rafael (Esteban Mur) (Hospital Universitari Vall d'Hebron)
Riveiro Barciela, Mar (Hospital Universitari Vall d'Hebron)
Buti, Maria (Hospital Universitari Vall d'Hebron)
Rodríguez Frías, Francisco (Hospital Universitari Vall d'Hebron)
Universitat Autònoma de Barcelona

Data:	2019
Resum:	BACKGROUND Hepatitis delta virus (HDV) seems to strongly suppress hepatitis B virus (HBV) replication, although little is known about the mechanism of this interaction. Both these viruses show a dynamic distribution of mutants, resulting in viral quasispecies. Next-generation sequencing is a viable approach for analyzing the composition of these mutant spectra. As the regulatory hepatitis B X protein (HBx) is essential for HBV replication, determination of HBV X gene (HBX) quasispecies complexity in HBV/HDV infection compared to HBV mono-infection may provide information on the interactions between these two viruses. AIM To compare HBV quasispecies complexity in the HBX 5' region between chronic hepatitis delta (CHD) and chronic HBV mono-infected patients. METHODS Twenty-four untreated patients were included: 7/24 (29. 2%) with HBeAg-negative chronic HBV infection (CI, previously termed inactive carriers), 8/24 (33. 3%) with HBeAg-negative chronic hepatitis B (CHB) and 9/24 (37. 5%) with CHD. A serum sample from each patient was first tested for HBV DNA levels. The HBX 5' region [nucleotides (nt) 1255-1611] was then PCR-amplified for subsequent next-generation sequencing (MiSeq, Illumina, United States). HBV quasispecies complexity in the region analyzed was evaluated using incidence-based indices (number of haplotypes and number of mutations), abundance-based indices (Hill numbers of order 1 and 2), and functional indices (mutation frequency and nucleotide diversity). We also evaluated the pattern of nucleotide changes to investigate which of them could be the cause of the quasispecies complexity. RESULTS CHB patients showed higher median HBV-DNA levels [5. 4 logIU/mL, interquartile range (IQR) 3. 5-7. 9] than CHD (3. 4 logIU/mL, IQR 3-7. 6) (P = n. s. ) or CI (3. 2 logIU/mL, IQR 2. 3-3. 5) (P < 0. 01) patients. The incidence and abundance indices indicated that HBV quasispecies complexity was significantly greater in CI than CHB. A similar trend was observed in CHD patients, although only Hill numbers of order 2 showed statistically significant differences (CHB 2. 81, IQR 1. 11-4. 57 vs CHD 8. 87, 6. 56-11. 18, P = 0. 038). There were no significant differences in the functional indices, but CI and CHD patients also showed a trend towards greater complexity than CHB. No differences were found for any HBV quasispecies complexity indices between CHD and CI patients. G-to-A and C-to-T nucleotide changes, characteristic of APOBEC3G, were higher in CHD and CI than in CHB in genotype A haplotypes, but not in genotype D. The proportion of nt G-to-A vs A-to-G changes and C-to-T vs T-to-C changes in genotype A and D haplotypes in CHD patients showed no significant differences. In CHB and CI the results of these comparisons were dependent on HBV genotype. CONCLUSION The lower-replication CHD and CI groups show a trend to higher quasispecies complexity than the higher-replication CHB group. The mechanisms associated with this greater complexity require elucidation.
Ajuts:	Instituto de Salud Carlos III PI15/00856 Instituto de Salud Carlos III PI17/02233
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Hepatitis B virus ; Hepatitis delta virus ; Hepatitis B X gene ; Next-generation sequencing ; Viral quasispecies ; Hepatitis B virus-hepatitis delta virus interaction
Publicat a:	World Journal of Gastroenterology, Vol. 25 (april 2019) , p. 1566-1579, ISSN 2219-2840

DOI: 10.3748/wjg.v25.i13.1566
PMID: 30983817

18 p, 2.2 MB

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