title: Virus evolution during chronic hepatitis B virus infection as revealed by ultradeep sequencing data.
abstract: Despite chronic hepatitis B virus (HBV) infection (CHB) being a leading cause of liver cirrhosis and cancer, HBV evolution during CHB is not fully understood. Recent studies have indicated that virus diversity progressively increases along the course of CHB and that some virus mutations correlate with severe liver conditions such as chronic hepatitis, cirrhosis and hepatocellular carcinoma. Using ultradeep sequencing (UDS) data from an intrafamilial case, we detected such mutations at low frequencies among three immunotolerant patients and at high frequencies in an inactive carrier. Furthermore, our analyses indicated that the HBV population from the seroconverter patient underwent many genetic changes in response to virus clearance. Together, these data indicate a potential use of UDS for developing non-invasive biomarkers for monitoring disease changes over time or in response to specific therapies. In addition, our analyses revealed that virus clearance seemed not to require the virus effective population size to decline. A detailed genetic analysis of the viral lineages arising during and after the clearance suggested that mutations at or close to critical elements of the core promoter (enhancer II, epsilon encapsidation signal, TA2, TA3 and direct repeat 1-hormone response element) might be responsible for a sustained replication. This hypothesis requires the decline in virus load to be explained by constant clearance of virus-producing hepatocytes, consistent with the sustained progress towards serious liver conditions experienced by many CHB patients.
authors.affiliation: Laboratorio de Virología y Genética Molecular, Facultad de Ciencias Naturales sede Trelew, Universidad Nacional de la Patagonia San Juan Bosco, 9 de Julio y Begrano S/N (9100) Trelew, Chubut, Argentina.|Consejo Nacional de Investigaciones Científicas y Técnicas, Av. Rivadavia 1917 (C1083ACA) Buenos Aires, Argentina.
authors.forename: Leandro R
authors.initials: LR
authors.lastname: Jones
authors.affiliation: Consejo Nacional de Investigaciones Científicas y Técnicas, Av. Rivadavia 1917 (C1083ACA) Buenos Aires, Argentina.|Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155-Piso 11 (C1121ABG) Buenos Aires, Argentina.
authors.forename: Mariano
authors.initials: M
authors.lastname: Sede
authors.affiliation: Consejo Nacional de Investigaciones Científicas y Técnicas, Av. Rivadavia 1917 (C1083ACA) Buenos Aires, Argentina.|Laboratorio de Virología y Genética Molecular, Facultad de Ciencias Naturales sede Trelew, Universidad Nacional de la Patagonia San Juan Bosco, 9 de Julio y Begrano S/N (9100) Trelew, Chubut, Argentina.
authors.forename: Julieta M
authors.initials: JM
authors.lastname: Manrique
authors.affiliation: Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155-Piso 11 (C1121ABG) Buenos Aires, Argentina.|Consejo Nacional de Investigaciones Científicas y Técnicas, Av. Rivadavia 1917 (C1083ACA) Buenos Aires, Argentina.
authors.forename: Jorge
authors.initials: J
authors.lastname: Quarleri
mesh_terms: D002648:Child; D016000:Cluster Analysis; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D019143:Evolution, Molecular; D005192:Family Health; D005260:Female; D014644:Genetic Variation; D006515:Hepatitis B virus / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification; D019694:Hepatitis B, Chronic / Q000821:virology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D017385:Sequence Homology
chemical_list: D004279:DNA, Viral