Immune-escape mutations and stop-codons in HBsAg develop in a large proportion of patients with chronic HBV infection exposed to anti-HBV drugs in Europe.

Autor: Colagrossi L; Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy., Hermans LE; Virology, Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands.; Department of Viroscience, Erasmus Medical Centre, Rotterdam, The Netherlands., Salpini R; Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy., Di Carlo D; Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy., Pas SD; Department of Viroscience, Erasmus Medical Centre, Rotterdam, The Netherlands., Alvarez M; Servicio de Microbiología, Hospital San Cecilio, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada, Granada, Spain., Ben-Ari Z; Liver Disease Centre, Sheba Medical Centre, Ramat Gan, Israel., Boland G; Virology, Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands., Bruzzone B; Hygiene Unit, IRCCS AOU San Martino - IST, Genoa, Italy., Coppola N; Malattie Infettive, Seconda Università degli studi di Napoli, Naples, Italy., Seguin-Devaux C; Laboratory of Retrovirology, CRP-Santé, Luxembourg, Luxembourg., Dyda T; Molecular Diagnostics Laboratory, Hospital of Infectious Diseases, Warsaw, Poland., Garcia F; Servicio de Microbiología, Hospital San Cecilio, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada, Granada, Spain., Kaiser R; Institute of Virology, University of Cologne, Cologne, Germany., Köse S; Izmir Tepecik Education and Research Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Izmir, Turkey., Krarup H; Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark., Lazarevic I; Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia., Lunar MM; Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia., Maylin S; Service de Microbiologie, University Paris Diderot, Hôpital Saint Louis, Paris, France., Micheli V; L. Sacco Hospital, Milan, Italy., Mor O; National HIV Reference Laboratory, Central Virology Laboratory, Ministry of Health, Tel Hashomer, Ramat Gan, Israel., Paraschiv S; Molecular Diagnostics Laboratory, National Institute for Infectious Diseases 'Matei Bals', Bucharest, Romania., Paraskevis D; National Retrovirus Reference Centre, Department of Hygiene, Epidemiology and Medical Statistics, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece., Poljak M; Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia., Puchhammer-Stöckl E; Department for Virology, Medical University of Vienna, Vienna, Austria., Simon F; Service de Microbiologie, University Paris Diderot, Hôpital Saint Louis, Paris, France., Stanojevic M; Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia., Stene-Johansen K; Department of Virology, Norwegian Institute of Public Health, Oslo, Norway., Tihic N; Institute of Microbiology, Polyclinic for Laboratory Diagnostics, University Clinical Centre Tuzla, Tuzla, Bosnia and Herzegovina., Trimoulet P; Virology Laboratory, Centre Hospitalier Régional et Université 'Victor Segalen', Bordeaux, France., Verheyen J; Institute of Virology, University-Hospital, University Duisburg-Essen, Essen, Germany., Vince A; University of Zagreb School of Medicine and University Hospital for Infectious Diseases, Zagreb, Croatia., Lepej SZ; University of Zagreb School of Medicine and University Hospital for Infectious Diseases, Zagreb, Croatia., Weis N; Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark., Yalcinkaya T; Refik Saydam National Public Health Agency, Ankara, Turkey., Boucher CAB; Department of Viroscience, Erasmus Medical Centre, Rotterdam, The Netherlands., Wensing AMJ; Virology, Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands., Perno CF; Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy. cf.perno@uniroma2.it., Svicher V; Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy. valentina.svicher@uniroma2.it.
Jazyk: angličtina
Zdroj: BMC infectious diseases [BMC Infect Dis] 2018 Jun 01; Vol. 18 (1), pp. 251. Date of Electronic Publication: 2018 Jun 01.
DOI: 10.1186/s12879-018-3161-2
Abstrakt: Background: HBsAg immune-escape mutations can favor HBV-transmission also in vaccinated individuals, promote immunosuppression-driven HBV-reactivation, and increase fitness of drug-resistant strains. Stop-codons can enhance HBV oncogenic-properties. Furthermore, as a consequence of the overlapping structure of HBV genome, some immune-escape mutations or stop-codons in HBsAg can derive from drug-resistance mutations in RT. This study is aimed at gaining insight in prevalence and characteristics of immune-associated escape mutations, and stop-codons in HBsAg in chronically HBV-infected patients experiencing nucleos(t)ide analogues (NA) in Europe.
Methods: This study analyzed 828 chronically HBV-infected European patients exposed to ≥ 1 NA, with detectable HBV-DNA and with an available HBsAg-sequence. The immune-associated escape mutations and the NA-induced immune-escape mutations sI195M, sI196S, and sE164D (resulting from drug-resistance mutation rtM204 V, rtM204I, and rtV173L) were retrieved from literature and examined. Mutations were defined as an aminoacid substitution with respect to a genotype A or D reference sequence.
Results: At least one immune-associated escape mutation was detected in 22.1% of patients with rising temporal-trend. By multivariable-analysis, genotype-D correlated with higher selection of ≥ 1 immune-associated escape mutation (OR[95%CI]:2.20[1.32-3.67], P = 0.002). In genotype-D, the presence of ≥ 1 immune-associated escape mutations was significantly higher in drug-exposed patients with drug-resistant strains than with wild-type virus (29.5% vs 20.3% P = 0.012). Result confirmed by analysing drug-naïve patients (29.5% vs 21.2%, P = 0.032). Strong correlation was observed between sP120T and rtM204I/V (P < 0.001), and their co-presence determined an increased HBV-DNA. At least one NA-induced immune-escape mutation occurred in 28.6% of patients, and their selection correlated with genotype-A (OR[95%CI]:2.03[1.32-3.10],P = 0.001). Finally, stop-codons are present in 8.4% of patients also at HBsAg-positions 172 and 182, described to enhance viral oncogenic-properties.
Conclusions: Immune-escape mutations and stop-codons develop in a large fraction of NA-exposed patients from Europe. This may represent a potential threat for horizontal and vertical HBV transmission also to vaccinated persons, and fuel drug-resistance emergence.
Databáze: MEDLINE
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