Overlapping structure of hepatitis B virus (HBV) genome and immune selection pressure are critical forces modulating HBV evolution

J Gen Virol. 2013 Jan;94(Pt 1):143-149. doi: 10.1099/vir.0.046524-0. Epub 2012 Oct 10.

Abstract

How the overlap between the hepatitis B virus (HBV) reverse transcriptase (RT) and HBV S antigen (HBsAg) genes modulates the extent of HBV genetic variability is still an open question, and was investigated here. The rate of nucleotide conservation (≤1% variability) followed an atypical pattern in the RT gene, due to an overlap between RT and HBsAg (69.9% nucleotide conservation in the overlapping region vs 41.2% in the non-overlapping region; P<0.001), with a consequently lower rate of synonymous substitution within the overlapping region [median(interquartile range)dS=3.1(1.5-7.4) vs 20.1(10.6-30.0); P=3.249×10(-22)]. The most conserved RT regions were located within the YMDD motif and the N-terminal parts of the palm and finger domains, critical for RT functionality. These regions also corresponded to highly conserved HBsAg domains that are critical for HBsAg secretion. Conversely, the genomic region encoding the HBsAg antigenic loop (where immune-escape mutations are localized) showed a sharp decrease in the extent of conservation (40.6%), which was less pronounced in the setting of human immunodeficiency virus (HIV)-driven immune suppression (48.8% in HIV-HBV co-infection vs 21.5% in mono-infected patients; P=0.020). In conclusion, the overlapping reading frame and the immune system appear to have shaped the patterns of RT and HBsAg genetic variability. Highly conserved regions in RT and HBsAg may deserve further attention as novel therapeutic targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Coinfection / genetics
  • Coinfection / immunology
  • Evolution, Molecular
  • Genetic Variation
  • Genome, Viral*
  • HIV / genetics
  • HIV / immunology
  • HIV Infections / genetics
  • HIV Infections / immunology
  • HIV Infections / virology
  • Hepatitis B Surface Antigens / genetics
  • Hepatitis B Surface Antigens / immunology
  • Hepatitis B virus / genetics*
  • Hepatitis B virus / immunology*
  • Hepatitis B, Chronic / genetics*
  • Hepatitis B, Chronic / immunology*
  • Hepatitis B, Chronic / virology
  • Humans
  • Molecular Sequence Data
  • Mutation / immunology
  • RNA-Directed DNA Polymerase / genetics
  • RNA-Directed DNA Polymerase / immunology

Substances

  • Hepatitis B Surface Antigens
  • RNA-Directed DNA Polymerase

Associated data

  • GENBANK/JX849204
  • GENBANK/JX849205
  • GENBANK/JX849206
  • GENBANK/JX849207
  • GENBANK/JX849208
  • GENBANK/JX849209
  • GENBANK/JX849210
  • GENBANK/JX849211
  • GENBANK/JX849212
  • GENBANK/JX849213
  • GENBANK/JX849214
  • GENBANK/JX849215
  • GENBANK/JX849216
  • GENBANK/JX849217
  • GENBANK/JX849218
  • GENBANK/JX849219
  • GENBANK/JX849220
  • GENBANK/JX849221
  • GENBANK/JX849222
  • GENBANK/JX849223
  • GENBANK/JX849224
  • GENBANK/JX849225
  • GENBANK/JX849226
  • GENBANK/JX849227
  • GENBANK/JX849228
  • GENBANK/JX849229
  • GENBANK/JX849230
  • GENBANK/JX849231
  • GENBANK/JX849232
  • GENBANK/JX849233
  • GENBANK/JX849234
  • GENBANK/JX849235
  • GENBANK/JX849236
  • GENBANK/JX849237
  • GENBANK/JX849238
  • GENBANK/JX849239
  • GENBANK/JX849240
  • GENBANK/JX849241
  • GENBANK/JX849242
  • GENBANK/JX849243
  • GENBANK/JX849244
  • GENBANK/JX849245
  • GENBANK/JX849246
  • GENBANK/JX849247
  • GENBANK/JX849248
  • GENBANK/JX849249
  • GENBANK/JX849250
  • GENBANK/JX849251
  • GENBANK/JX849252
  • GENBANK/JX849253
  • GENBANK/JX849254
  • GENBANK/JX849255
  • GENBANK/JX849256
  • GENBANK/JX849257
  • GENBANK/JX849258
  • GENBANK/JX849259
  • GENBANK/JX849260
  • GENBANK/JX849261
  • GENBANK/JX849262
  • GENBANK/JX849263
  • GENBANK/JX849264
  • GENBANK/JX849265
  • GENBANK/JX849266
  • GENBANK/JX849267
  • GENBANK/JX849268
  • GENBANK/JX849269
  • GENBANK/JX849270
  • GENBANK/JX849271
  • GENBANK/JX849272
  • GENBANK/JX849273
  • GENBANK/JX849274
  • GENBANK/JX849275
  • GENBANK/JX849276
  • GENBANK/JX849277
  • GENBANK/JX849278
  • GENBANK/JX849279
  • GENBANK/JX849280
  • GENBANK/JX849281
  • GENBANK/JX849282
  • GENBANK/JX849283
  • GENBANK/JX849284
  • GENBANK/JX849285
  • GENBANK/JX849286
  • GENBANK/JX849287
  • GENBANK/JX849288
  • GENBANK/JX849289
  • GENBANK/JX849290
  • GENBANK/JX849291
  • GENBANK/JX849292
  • GENBANK/JX849293
  • GENBANK/JX849294
  • GENBANK/JX849295
  • GENBANK/JX849296
  • GENBANK/JX849297
  • GENBANK/JX849298
  • GENBANK/JX849299
  • GENBANK/JX849300
  • GENBANK/JX849301
  • GENBANK/JX849302
  • GENBANK/JX849303
  • GENBANK/JX849304
  • GENBANK/JX849305
  • GENBANK/JX849306
  • GENBANK/JX849307
  • GENBANK/JX849308
  • GENBANK/JX849309
  • GENBANK/JX849310
  • GENBANK/JX849311
  • GENBANK/JX849312
  • GENBANK/JX849313
  • GENBANK/JX849314
  • GENBANK/JX849315
  • GENBANK/JX849316
  • GENBANK/JX849317
  • GENBANK/JX849318
  • GENBANK/JX849319
  • GENBANK/JX849320
  • GENBANK/JX849321
  • GENBANK/JX849322
  • GENBANK/JX849323
  • GENBANK/JX849324
  • GENBANK/JX849325
  • GENBANK/JX849326
  • GENBANK/JX849327
  • GENBANK/JX849328
  • GENBANK/JX849329
  • GENBANK/JX849330
  • GENBANK/JX849331
  • GENBANK/JX849332
  • GENBANK/JX849333
  • GENBANK/JX849334
  • GENBANK/JX849335
  • GENBANK/JX849336
  • GENBANK/JX849337
  • GENBANK/JX849338
  • GENBANK/JX849339
  • GENBANK/JX849340
  • GENBANK/JX849341
  • GENBANK/JX849342
  • GENBANK/JX849343
  • GENBANK/JX849344
  • GENBANK/JX849345
  • GENBANK/JX849346
  • GENBANK/JX849347
  • GENBANK/JX849348
  • GENBANK/JX849349
  • GENBANK/JX849350
  • GENBANK/JX849351
  • GENBANK/JX849352
  • GENBANK/JX849353
  • GENBANK/JX849354
  • GENBANK/JX849355
  • GENBANK/JX849356
  • GENBANK/JX849357
  • GENBANK/JX849358
  • GENBANK/JX849359
  • GENBANK/JX849360
  • GENBANK/JX849361
  • GENBANK/JX849362
  • GENBANK/JX849363
  • GENBANK/JX849364
  • GENBANK/JX849365
  • GENBANK/JX849366
  • GENBANK/JX849367
  • GENBANK/JX849368
  • GENBANK/JX849369
  • GENBANK/JX849370
  • GENBANK/JX849371
  • GENBANK/JX849372
  • GENBANK/JX849373
  • GENBANK/JX849374
  • GENBANK/JX849375
  • GENBANK/JX849376
  • GENBANK/JX849377
  • GENBANK/JX849378
  • GENBANK/JX849379
  • GENBANK/JX849380
  • GENBANK/JX849381
  • GENBANK/JX849382
  • GENBANK/JX849383
  • GENBANK/JX849384
  • GENBANK/JX849385
  • GENBANK/JX849386
  • GENBANK/JX849387
  • GENBANK/JX849388
  • GENBANK/JX849389
  • GENBANK/JX849390
  • GENBANK/JX849391
  • GENBANK/JX849392
  • GENBANK/JX849393
  • GENBANK/JX849394
  • GENBANK/JX849395
  • GENBANK/JX849396
  • GENBANK/JX849397
  • GENBANK/JX849398
  • GENBANK/JX849399
  • GENBANK/JX849400
  • GENBANK/JX849401
  • GENBANK/JX849402
  • GENBANK/JX849403
  • GENBANK/JX849404
  • GENBANK/JX849405
  • GENBANK/JX849406
  • GENBANK/JX849407
  • GENBANK/JX849408
  • GENBANK/JX849409
  • GENBANK/JX849410
  • GENBANK/JX849411
  • GENBANK/JX849412
  • GENBANK/JX849413
  • GENBANK/JX849414
  • GENBANK/JX849415
  • GENBANK/JX849416
  • GENBANK/JX849417
  • GENBANK/JX849418
  • GENBANK/JX849419
  • GENBANK/JX849420
  • GENBANK/JX849421
  • GENBANK/JX849422
  • GENBANK/JX849423
  • GENBANK/JX849424
  • GENBANK/JX849425
  • GENBANK/JX849426
  • GENBANK/JX849427
  • GENBANK/JX849428
  • GENBANK/JX849429
  • GENBANK/JX849430
  • GENBANK/JX849431
  • GENBANK/JX849432
  • GENBANK/JX849433
  • GENBANK/JX849434
  • GENBANK/JX849435
  • GENBANK/JX849436
  • GENBANK/JX849437
  • GENBANK/JX849438
  • GENBANK/JX849439
  • GENBANK/JX849440
  • GENBANK/JX849441
  • GENBANK/JX849442
  • GENBANK/JX849443
  • GENBANK/JX849444
  • GENBANK/JX849445
  • GENBANK/JX849446
  • GENBANK/JX849447
  • GENBANK/JX849448
  • GENBANK/JX849449
  • GENBANK/JX849450
  • GENBANK/JX849451
  • GENBANK/JX849452
  • GENBANK/JX849453
  • GENBANK/JX849454
  • GENBANK/JX849455
  • GENBANK/JX849456
  • GENBANK/JX849457
  • GENBANK/JX849458
  • GENBANK/JX849459
  • GENBANK/JX849460
  • GENBANK/JX849461
  • GENBANK/JX849462
  • GENBANK/JX849463
  • GENBANK/JX849464
  • GENBANK/JX849465
  • GENBANK/JX849466
  • GENBANK/JX849467
  • GENBANK/JX849468
  • GENBANK/JX849469
  • GENBANK/JX849470
  • GENBANK/JX849471
  • GENBANK/JX849472
  • GENBANK/JX849473
  • GENBANK/JX849474
  • GENBANK/JX849475
  • GENBANK/JX849476
  • GENBANK/JX849477
  • GENBANK/JX849478
  • GENBANK/JX849479
  • GENBANK/JX849480
  • GENBANK/JX849481
  • GENBANK/JX849482
  • GENBANK/JX849483
  • GENBANK/JX849484
  • GENBANK/JX849485
  • GENBANK/JX849486
  • GENBANK/JX849487
  • GENBANK/JX849488
  • GENBANK/JX849489
  • GENBANK/JX849490
  • GENBANK/JX849491
  • GENBANK/JX849492
  • GENBANK/JX849493
  • GENBANK/JX849494
  • GENBANK/JX849495
  • GENBANK/JX849496
  • GENBANK/JX849497
  • GENBANK/JX849498
  • GENBANK/JX849499
  • GENBANK/JX849500
  • GENBANK/JX849501
  • GENBANK/JX849502
  • GENBANK/JX849503
  • GENBANK/JX849504
  • GENBANK/JX849505
  • GENBANK/JX849506
  • GENBANK/JX849507
  • GENBANK/JX849508
  • GENBANK/JX849509
  • GENBANK/JX849510
  • GENBANK/JX849511
  • GENBANK/JX849512
  • GENBANK/JX849513
  • GENBANK/JX849514
  • GENBANK/JX849515
  • GENBANK/JX849516
  • GENBANK/JX849517
  • GENBANK/JX849518
  • GENBANK/JX849519
  • GENBANK/JX849520
  • GENBANK/JX849521
  • GENBANK/JX849522
  • GENBANK/JX849523
  • GENBANK/JX849524
  • GENBANK/JX849525
  • GENBANK/JX849526
  • GENBANK/JX849527
  • GENBANK/JX849528
  • GENBANK/JX849529
  • GENBANK/JX849530
  • GENBANK/JX849531
  • GENBANK/JX849532
  • GENBANK/JX849533
  • GENBANK/JX849534
  • GENBANK/JX849535
  • GENBANK/JX849536
  • GENBANK/JX849537
  • GENBANK/JX849538
  • GENBANK/JX849539
  • GENBANK/JX849540
  • GENBANK/JX849541
  • GENBANK/JX849542
  • GENBANK/JX849543
  • GENBANK/JX849544
  • GENBANK/JX849545
  • GENBANK/JX849546
  • GENBANK/JX849547
  • GENBANK/JX849548
  • GENBANK/JX849549
  • GENBANK/JX849550
  • GENBANK/JX849551
  • GENBANK/JX849552
  • GENBANK/JX849553
  • GENBANK/JX849554
  • GENBANK/JX849555
  • GENBANK/JX849556
  • GENBANK/JX849557
  • GENBANK/JX849558
  • GENBANK/JX849559
  • GENBANK/JX849560
  • GENBANK/JX849561
  • GENBANK/JX849562
  • GENBANK/JX849563
  • GENBANK/JX849564
  • GENBANK/JX849565
  • GENBANK/JX849566
  • GENBANK/JX849567
  • GENBANK/JX849568
  • GENBANK/JX849569
  • GENBANK/JX849570
  • GENBANK/JX849571
  • GENBANK/JX849572
  • GENBANK/JX849573
  • GENBANK/JX849574
  • GENBANK/JX849575
  • GENBANK/JX849576
  • GENBANK/JX849577
  • GENBANK/JX849578
  • GENBANK/JX849579
  • GENBANK/JX849580
  • GENBANK/JX849581
  • GENBANK/JX849582
  • GENBANK/JX849583
  • GENBANK/JX849584
  • GENBANK/JX849585
  • GENBANK/JX849586
  • GENBANK/JX849587
  • GENBANK/JX849588
  • GENBANK/JX849589
  • GENBANK/JX849590
  • GENBANK/JX849591
  • GENBANK/JX849592
  • GENBANK/JX849593
  • GENBANK/JX849594
  • GENBANK/JX849595
  • GENBANK/JX849596
  • GENBANK/JX849597
  • GENBANK/JX849598
  • GENBANK/JX849599
  • GENBANK/JX849600
  • GENBANK/JX849601
  • GENBANK/JX849602
  • GENBANK/JX849603
  • GENBANK/JX849604
  • GENBANK/JX849605
  • GENBANK/JX849606
  • GENBANK/JX849607
  • GENBANK/JX849608
  • GENBANK/JX849609
  • GENBANK/JX849610
  • GENBANK/JX849611
  • GENBANK/JX849612
  • GENBANK/JX849613
  • GENBANK/JX849614
  • GENBANK/JX849615
  • GENBANK/JX849616
  • GENBANK/JX849617
  • GENBANK/JX849618
  • GENBANK/JX849619
  • GENBANK/JX849620
  • GENBANK/JX849621
  • GENBANK/JX849622
  • GENBANK/JX849623
  • GENBANK/JX849624
  • GENBANK/JX849625
  • GENBANK/JX849626
  • GENBANK/JX849627
  • GENBANK/JX849628
  • GENBANK/JX849629
  • GENBANK/JX849630
  • GENBANK/JX849631
  • GENBANK/JX849632
  • GENBANK/JX849633
  • GENBANK/JX849634
  • GENBANK/JX849635
  • GENBANK/JX849636
  • GENBANK/JX849637
  • GENBANK/JX849638
  • GENBANK/JX849639
  • GENBANK/JX849640
  • GENBANK/JX849641
  • GENBANK/JX849642
  • GENBANK/JX849643
  • GENBANK/JX849644
  • GENBANK/JX849645
  • GENBANK/JX849646
  • GENBANK/JX849647