0 8 Enhanced enhance VBN 9 23 responsiveness responsiveness NN 24 26 to to TO 27 34 nuclear nuclear JJ 35 41 factor factor NN 42 47 kappa kappa NN 48 49 B B NNP 50 61 contributes contribute VBZ 62 64 to to TO 65 68 the the DT 69 75 unique unique JJ 76 85 phenotype phenotype NN 86 88 of of IN 89 95 simian simian JJ 96 112 immunodeficiency immunodeficiency NN 113 118 virus virus NN 119 126 variant variant JJ 127 138 SIVsmmPBj14 sivsmmpbj14 NN 138 139 . . . 141 150 Infection infection NN 151 155 with with IN 156 157 a a DT 158 165 variant variant NN 166 168 of of IN 169 175 simian simian JJ 176 192 immunodeficiency immunodeficiency NN 193 198 virus virus NN 198 199 , , , 200 211 SIVsmmPBj14 sivsmmpbj14 NN 211 212 , , , 213 218 leads lead VBZ 219 221 to to TO 222 228 severe severe JJ 229 234 acute acute JJ 235 242 disease disease NN 243 245 in in IN 246 254 macaques macaque NNS 254 255 . . . 256 260 This this DT 261 266 study study NN 267 270 was be VBD 271 279 designed design VBN 280 282 to to TO 283 294 investigate investigate VB 295 298 the the DT 299 309 functional functional JJ 310 322 significance significance NN 323 325 of of IN 326 336 previously previously RB 337 346 described describe VBN 347 356 mutations mutation NNS 357 359 in in IN 360 363 the the DT 364 369 viral viral JJ 370 374 long long JJ 375 383 terminal terminal JJ 384 390 repeat repeat NN 391 392 ( ( ( 392 395 LTR LTR NNP 395 396 ) ) ) 397 400 and and CC 401 403 to to TO 404 413 elucidate elucidate VB 414 419 their their PRP$ 420 432 contribution contribution NN 433 435 to to TO 436 439 the the DT 440 446 unique unique JJ 447 456 phenotype phenotype NN 457 459 of of IN 460 471 SIVsmmPBj14 sivsmmpbj14 NN 471 472 . . . 473 485 LTR-directed ltr-directed JJ 486 499 transcription transcription NN 500 503 was be VBD 504 512 measured measure VBN 513 515 by by IN 516 521 using use VBG 522 532 luciferase luciferase NN 533 541 reporter reporter NN 542 552 constructs construct NNS 553 557 that that WDT 558 562 were be VBD 563 574 transiently transiently RB 575 586 transfected transfecte VBN 587 591 into into IN 592 600 cultured culture VBN 601 606 cells cell NNS 606 607 . . . 608 610 In in IN 611 612 a a DT 613 617 wide wide JJ 618 623 range range NN 624 626 of of IN 627 631 cell cell NN 632 637 types type NNS 637 638 , , , 639 642 the the DT 643 648 basal basal JJ 649 664 transcriptional transcriptional JJ 665 673 activity activity NN 674 676 of of IN 677 680 the the DT 681 684 LTR ltr NN 685 689 from from IN 690 701 SIVsmmPBj14 sivsmmpbj14 NN 702 705 was be VBD 706 711 found find VBN 712 714 to to TO 715 717 be be VB 718 720 2- 2- CD 721 723 to to TO 724 732 4.5-fold 4.5-fold RB 733 739 higher high JJR 740 744 than than IN 745 749 that that DT 750 752 of of IN 753 755 an an DT 756 759 LTR ltr NN 760 764 from from IN 765 766 a a DT 767 778 non-acutely non-acutely JJ 779 789 pathogenic pathogenic JJ 790 796 strain strain NN 796 797 . . . 798 803 These these DT 804 808 LTRs LTR NNPS 809 815 differ differ VBP 816 818 by by IN 819 823 five five CD 824 829 point point NN 830 839 mutations mutation NNS 840 843 and and CC 844 845 a a DT 846 851 22-bp 22-bp JJ 852 863 duplication duplication NN 864 866 in in IN 867 878 SIVsmmPBj14 sivsmmpbj14 NN 878 879 , , , 880 885 which which WDT 886 894 includes include VBZ 895 896 a a DT 897 904 nuclear nuclear JJ 905 911 factor factor NN 912 917 kappa kappa NN 918 919 B B NNP 920 921 ( ( ( 921 923 NF NF NNP 924 929 kappa kappa NN 930 931 B B NNP 931 932 ) ) ) 933 937 site site NN 937 938 . . . 939 954 Transcriptional transcriptional JJ 955 966 differences difference NNS 967 974 between between IN 975 980 these these DT 981 985 LTRs ltr NNS 986 990 were be VBD 991 998 further further RB 999 1007 enhanced enhance VBN 1008 1010 by by IN 1011 1015 two- two- CD 1016 1018 to to TO 1019 1028 threefold threefold RB 1029 1033 upon upon IN 1034 1043 treatment treatment NN 1044 1046 of of IN 1047 1052 cells cell NNS 1053 1057 with with IN 1058 1065 phorbol phorbol NN 1066 1071 ester ester NN 1072 1074 or or CC 1075 1080 tumor tumor NN 1081 1089 necrosis necrosis NN 1090 1096 factor factor NN 1097 1102 alpha alpha NN 1103 1105 or or CC 1106 1108 by by IN 1109 1123 cotransfection cotransfection NN 1124 1128 with with IN 1129 1137 plasmids plasmid NNS 1138 1148 expressing express VBG 1149 1151 NF NF NNP 1152 1157 kappa kappa NN 1158 1159 B B NNP 1160 1168 subunits subunit NNS 1168 1169 . . . 1170 1181 Mutagenesis Mutagenesis NNP 1182 1189 studies study NNS 1189 1190 , , , 1191 1194 and and CC 1195 1198 the the DT 1199 1202 use use NN 1203 1205 of of IN 1206 1207 a a DT 1208 1216 reporter reporter NN 1217 1226 construct construct NN 1227 1237 containing contain VBG 1238 1240 an an DT 1241 1253 enhancerless enhancerless JJ 1254 1262 promoter promoter NN 1262 1263 , , , 1264 1272 indicate indicate VBP 1273 1277 that that IN 1278 1283 these these DT 1284 1299 transcriptional transcriptional JJ 1300 1307 effects effect NNS 1308 1311 are be VBP 1312 1315 due due JJ 1316 1327 principally principally RB 1328 1330 to to TO 1331 1334 the the DT 1335 1340 22-bp 22-bp JJ 1341 1349 sequence sequence NN 1350 1361 duplication duplication NN 1362 1365 and and CC 1366 1369 the the DT 1370 1372 NF NF NNP 1373 1378 kappa kappa NN 1379 1380 B B NNP 1381 1385 site site NN 1386 1395 contained contain VBN 1396 1402 within within IN 1403 1405 it it PRP 1405 1406 . . . 1407 1414 Finally finally RB 1414 1415 , , , 1416 1426 infectious infectious JJ 1427 1432 virus virus NN 1433 1439 stocks stock NNS 1440 1444 that that WDT 1445 1449 were be VBD 1450 1458 isogenic isogenic JJ 1459 1465 except except IN 1466 1469 for for IN 1470 1473 the the DT 1474 1477 LTR ltr NN 1478 1482 were be VBD 1483 1492 generated generate VBN 1492 1493 . . . 1494 1497 The the DT 1498 1501 LTR ltr NN 1502 1506 from from IN 1507 1518 SIVsmmPBj14 sivsmmpbj14 NN 1519 1522 was be VBD 1523 1528 found find VBN 1529 1531 to to TO 1532 1538 confer confer VB 1539 1541 an an DT 1542 1550 increase increase NN 1551 1553 in in IN 1554 1557 the the DT 1558 1566 kinetics kinetic NNS 1567 1569 of of IN 1570 1575 virus virus NN 1576 1587 replication replication NN 1588 1590 in in IN 1591 1599 cultured culture VBN 1600 1605 cells cell NNS 1605 1606 . . . 1607 1616 Inclusion inclusion NN 1617 1619 of of IN 1620 1624 this this DT 1625 1628 LTR ltr NN 1629 1631 in in IN 1632 1643 recombinant recombinant JJ 1644 1648 SIVs siv NNS 1649 1653 also also RB 1654 1662 resulted result VBD 1663 1665 in in IN 1666 1667 a a DT 1668 1672 two- two- CD 1673 1675 to to TO 1676 1685 threefold threefold JJ 1686 1690 rise rise NN 1691 1693 in in IN 1694 1697 the the DT 1698 1704 extent extent NN 1705 1707 of of IN 1708 1716 cellular cellular JJ 1717 1730 proliferation proliferation NN 1731 1735 that that WDT 1736 1739 was be VBD 1740 1747 induced induce VBN 1748 1750 in in IN 1751 1760 quiescent quiescent JJ 1761 1767 simian simian JJ 1768 1778 peripheral peripheral JJ 1779 1784 blood blood NN 1785 1796 mononuclear mononuclear JJ 1797 1802 cells cell NNS 1802 1803 . . . 1804 1809 These these DT 1810 1817 studies study NNS 1818 1821 are be VBP 1822 1832 consistent consistent JJ 1833 1837 with with IN 1838 1841 the the DT 1842 1852 hypothesis hypothesis NN 1853 1857 that that IN 1858 1861 LTR LTR NNP 1862 1871 mutations mutation NNS 1872 1878 assist assist VBP 1879 1890 SIVsmmPBj14 sivsmmpbj14 NN 1891 1893 in in IN 1894 1904 responding respond VBG 1905 1916 efficiently efficiently RB 1917 1919 to to TO 1920 1928 cellular cellular JJ 1929 1940 stimulation stimulation NN 1941 1944 and and CC 1945 1950 allow allow VB 1951 1953 it it PRP 1954 1956 to to TO 1957 1966 replicate replicate VB 1967 1969 to to TO 1970 1974 high high JJ 1975 1981 titers titer NNS 1982 1988 during during IN 1989 1992 the the DT 1993 1998 acute acute JJ 1999 2004 phase phase NN 2005 2007 of of IN 2008 2013 viral viral JJ 2014 2023 infection infection NN 2023 2024 . . .