Anti-human immunodeficiency virus type 1 activity of an oligocationic compound mediated via gp120 V3 interactions

被引:74
作者
OBrien, WA
SumnerSmith, M
Mao, SH
Sadeghi, S
Zhao, JQ
Chen, IY
机构
[1] UNIV CALIF LOS ANGELES,SCH MED,DEPT MED,LOS ANGELES,CA 90024
[2] UNIV CALIF LOS ANGELES,SCH MED,DEPT MICROBIOL & IMMUNOL,LOS ANGELES,CA 90024
[3] ALLELIX BIOPHARMACEUT INC,MISSISSAUGA,ON,CANADA
关键词
D O I
10.1128/JVI.70.5.2825-2831.1996
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
An oligocationic peptide compound (ALX40-4C) was developed for consideration in the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This compound was designed to mimic the basic domain of the HIV-1 transactivation protein, Tat, and will competitively,inhibit Tat binding to its specific RNA hairpin target (TAR [transactivation region]), found at the 5' end of all HIV-1 transcripts. Blocking Tat-TAR interactions can abrogate HIV-1 replication. ALX40-4C was shown to inhibit replication of HIV-1(NL4-3) in a range of cell types, including primary cells and transformed cell lines, by as much as 10(4)-fold. In some experiments, virus rescue was not possible even after removal of ALX40-4C from the cultures. Strain-dependent resistance has been demonstrated for all antiretroviral agents tested; therefore, we tested for variable sensitivity to ALX40-4C. The cloned primary strains, HIV-1(JR-CSF) and HIV-1(JR-FL,) ALX40-4C inhibition. Unexpectedly, determinants for efficient ALX40-4C inhibition were mapped by using recombinant virus strains to the V3 region of gp120 and were shown to act at early events in viral replication, which include viral entry. If entry and reverse transcription are bypassed by transfection, a more modest, virus strain-independent inhibition is shown; this inhibition is likely due to blocking of Tat-TAR interaction.'Thus, the highly basic oligocationic Tat inhibitor ALX40-4C appears to interfere with initial virus-target cell interactions which involve HIV-1 gp120 V3 determinants, most efficiently for T-cell line-adapted strains.
引用
收藏
页码:2825 / 2831
页数:7
相关论文
共 67 条
[51]   A SHORT-TERM CLINICAL-EVALUATION OF L-697,661, A NONNUCLEOSIDE INHIBITOR OF HIV-1 REVERSE-TRANSCRIPTASE [J].
SAAG, MS ;
EMINI, EA ;
LASKIN, OL ;
DOUGLAS, J ;
LAPIDUS, WI ;
SCHLEIF, WA ;
WHITLEY, RJ ;
HILDEBRAND, C ;
BYRNES, VW ;
KAPPES, JC ;
ANDERSON, KW ;
MASSARI, FE ;
SHAW, GM .
NEW ENGLAND JOURNAL OF MEDICINE, 1993, 329 (15) :1065-1072
[52]   CONFORMATIONAL-CHANGES INDUCED IN THE HUMAN-IMMUNODEFICIENCY-VIRUS ENVELOPE GLYCOPROTEIN BY SOLUBLE CD4 BINDING [J].
SATTENTAU, QJ ;
MOORE, JP .
JOURNAL OF EXPERIMENTAL MEDICINE, 1991, 174 (02) :407-415
[53]   RECOMBINANT SOLUBLE CD4 THERAPY IN PATIENTS WITH THE ACQUIRED-IMMUNODEFICIENCY-SYNDROME (AIDS) AND AIDS-RELATED COMPLEX - A PHASE-I PHASE-II ESCALATING DOSAGE TRIAL [J].
SCHOOLEY, RT ;
MERIGAN, TC ;
GAUT, P ;
HIRSCH, MS ;
HOLODNIY, M ;
FLYNN, T ;
LIU, S ;
BYINGTON, RE ;
HENOCHOWICZ, S ;
GUBISH, E ;
SPRIGGS, D ;
KUFE, D ;
SCHINDLER, J ;
DAWSON, A ;
THOMAS, D ;
HANSON, DG ;
LETWIN, B ;
LIU, T ;
GULINELLO, J ;
KENNEDY, S ;
FISHER, R ;
HO, DD .
ANNALS OF INTERNAL MEDICINE, 1990, 112 (04) :247-253
[54]   BIOLOGICAL PHENOTYPE OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 CLONES AT DIFFERENT STAGES OF INFECTION - PROGRESSION OF DISEASE IS ASSOCIATED WITH A SHIFT FROM MONOCYTOTROPIC TO T-CELL-TROPIC VIRUS POPULATIONS [J].
SCHUITEMAKER, H ;
KOOT, M ;
KOOTSTRA, NA ;
DERCKSEN, MW ;
DEGOEDE, REY ;
VANSTEENWIJK, RP ;
LANGE, JMA ;
SCHATTENKERK, JKME ;
MIEDEMA, F ;
TERSMETTE, M .
JOURNAL OF VIROLOGY, 1992, 66 (03) :1354-1360
[55]   MACROPHAGE AND T-CELL LINE TROPISMS OF HIV-1 ARE DETERMINED BY SPECIFIC REGIONS OF THE ENVELOPE GP120 GENE [J].
SHIODA, T ;
LEVY, JA ;
CHENGMAYER, C .
NATURE, 1991, 349 (6305) :167-169
[56]   LOCATION OF THE TRANS-ACTIVATING REGION ON THE GENOME OF HUMAN T-CELL LYMPHOTROPIC VIRUS TYPE-III [J].
SODROSKI, J ;
PATARCA, R ;
ROSEN, C ;
WONGSTAAL, F ;
HASELTINE, W .
SCIENCE, 1985, 229 (4708) :74-77
[57]  
SUMNERSMITH M, 1995, DRUG EXP CLIN RES, V21, P1
[58]  
SUMNERSMITH M, UNPUB
[59]  
SUMNERSMITH M, UNPUB ARGININE RICH
[60]   EVIDENCE FOR A ROLE OF VIRULENT HUMAN IMMUNODEFICIENCY VIRUS (HIV) VARIANTS IN THE PATHOGENESIS OF ACQUIRED IMMUNODEFICIENCY SYNDROME - STUDIES ON SEQUENTIAL HIV ISOLATES [J].
TERSMETTE, M ;
GRUTERS, RA ;
DEWOLF, F ;
DEGOEDE, REY ;
LANGE, JMA ;
SCHELLEKENS, PTA ;
GOUDSMIT, J ;
HUISMAN, HG ;
MIEDEMA, F .
JOURNAL OF VIROLOGY, 1989, 63 (05) :2118-2125