HBV-reactivation during immunosuppression can lead to severe acute hepatitis, fulminant liver failure, and death. Here, we investigated HBsAg genetic-features underlying this phenomenon by analyzing 93 patients: 29 developing HBV-reactivation, and 64 consecutive patients with chronic HBV-infection (as control). HBsAg genetic-diversity was analyzed by population-based and ultra-deep sequencing (UDS). Before HBV-reactivation, 51.7% of patients were isolated anti-HBc positive, 31.0% inactive carriers, 6.9% anti-HBc/anti-HBs positive, 6.9% isolated anti-HBs positive, and 3.4% had an overt HBV-infection. 51.7% of HBV-reactivated patients were treated with rituximab, 34.5% with different chemotherapeutics, and 13.8% with corticosteroids only for inflammatory-diseases. 75.9% of HBV-reactivated patients (versus 3.1% of control-patients, P<0.001) carried HBsAg-mutations localized in immune-active HBsAg regions. Of the 13 HBsAg-mutations found in these patients, 8/13 (M103I-L109I-T118K-P120A-Y134H-S143L-D144E-S171F) reside in major hydrophilic-loop (target of neutralizing-antibodies); some of them are already known to hamper HBsAg-recognition by humoral-response. The remaining 5 (C48G-V96A-L175S-G185E-V190A) are localized in Class-I/II-restricted T-cell epitopes, suggesting a role in HBV-escape from T-cell mediated responses. By UDS, these mutations occurred in HBV-reactivated patients with a median intra-patient prevalence of 73.3%(27.6%-100%) supporting their fixation in viral-population as predominant species. In control-patients carrying such mutations, their median intra-patient prevalence was 4.6%(2.5%-11.3%) (P<0.001). Finally, additional N-linked glycosylation-sites within major hydrophilic-loop were found in 24.1% of HBV-reactivated patients (versus 0% of chronic-patients, P<0.001); 5/7 patients carrying these sites remained HBsAg-negative despite HBV-reactivation. N-linked glycosylation can mask immunogenic-epitopes, abrogating HBsAg-recognition by antibodies. In conclusion, HBV-reactivation occurs in a wide variety of clinical-settings requiring immune-suppressive therapy, and correlates with HBsAg-mutations endowed with enhanced-capability to evade immune-response. This highlights the need of a careful patient's monitoring in all immunosuppressive-settings at reactivation-risk, and of establishing a prompt therapy to prevent HBV-related clinical complications.

Salpini, R., Colagrossi, L., Bellocchi, M., Surdo, M., Becker, C., Alteri, C., et al. (2015). Hepatitis B surface antigen genetic elements critical for immune escape correlate with hepatitis B virus reactivation upon immunosuppression. HEPATOLOGY, 61(3), 823-833 [10.1002/hep.27604].

Hepatitis B surface antigen genetic elements critical for immune escape correlate with hepatitis B virus reactivation upon immunosuppression

Salpini, R;Bellocchi, M;SARRECCHIA, CESARE;SARMATI, LOREDANA;ANDREONI, MASSIMO;ANGELICO, MARIO;PERNO, CARLO FEDERICO;SVICHER, VALENTINA
2015-11-01

Abstract

HBV-reactivation during immunosuppression can lead to severe acute hepatitis, fulminant liver failure, and death. Here, we investigated HBsAg genetic-features underlying this phenomenon by analyzing 93 patients: 29 developing HBV-reactivation, and 64 consecutive patients with chronic HBV-infection (as control). HBsAg genetic-diversity was analyzed by population-based and ultra-deep sequencing (UDS). Before HBV-reactivation, 51.7% of patients were isolated anti-HBc positive, 31.0% inactive carriers, 6.9% anti-HBc/anti-HBs positive, 6.9% isolated anti-HBs positive, and 3.4% had an overt HBV-infection. 51.7% of HBV-reactivated patients were treated with rituximab, 34.5% with different chemotherapeutics, and 13.8% with corticosteroids only for inflammatory-diseases. 75.9% of HBV-reactivated patients (versus 3.1% of control-patients, P<0.001) carried HBsAg-mutations localized in immune-active HBsAg regions. Of the 13 HBsAg-mutations found in these patients, 8/13 (M103I-L109I-T118K-P120A-Y134H-S143L-D144E-S171F) reside in major hydrophilic-loop (target of neutralizing-antibodies); some of them are already known to hamper HBsAg-recognition by humoral-response. The remaining 5 (C48G-V96A-L175S-G185E-V190A) are localized in Class-I/II-restricted T-cell epitopes, suggesting a role in HBV-escape from T-cell mediated responses. By UDS, these mutations occurred in HBV-reactivated patients with a median intra-patient prevalence of 73.3%(27.6%-100%) supporting their fixation in viral-population as predominant species. In control-patients carrying such mutations, their median intra-patient prevalence was 4.6%(2.5%-11.3%) (P<0.001). Finally, additional N-linked glycosylation-sites within major hydrophilic-loop were found in 24.1% of HBV-reactivated patients (versus 0% of chronic-patients, P<0.001); 5/7 patients carrying these sites remained HBsAg-negative despite HBV-reactivation. N-linked glycosylation can mask immunogenic-epitopes, abrogating HBsAg-recognition by antibodies. In conclusion, HBV-reactivation occurs in a wide variety of clinical-settings requiring immune-suppressive therapy, and correlates with HBsAg-mutations endowed with enhanced-capability to evade immune-response. This highlights the need of a careful patient's monitoring in all immunosuppressive-settings at reactivation-risk, and of establishing a prompt therapy to prevent HBV-related clinical complications.
nov-2015
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/17 - MALATTIE INFETTIVE
Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA
English
Con Impact Factor ISI
HBV; genetic variability; immunosuppression; surface antigen
Salpini, R., Colagrossi, L., Bellocchi, M., Surdo, M., Becker, C., Alteri, C., et al. (2015). Hepatitis B surface antigen genetic elements critical for immune escape correlate with hepatitis B virus reactivation upon immunosuppression. HEPATOLOGY, 61(3), 823-833 [10.1002/hep.27604].
Salpini, R; Colagrossi, L; Bellocchi, M; Surdo, M; Becker, C; Alteri, C; Aragri, M; Ricciardi, A; Armenia, D; Pollicita, M; Di Santo, F; Carioti, L; Louzoun, Y; Mastroianni, C; Lichtner, M; Paoloni, M; Esposito, M; D'Amore, C; Marrone, A; Marignani, M; Sarrecchia, C; Sarmati, L; Andreoni, M; Angelico, M; Verhejen, J; Perno, Cf; Svicher, V
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/99049
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