N-butyldeoxynojirimycin-mediated inhibition of human immunodeficiency virus entry correlates with impaired gp120 shedding and gp41 exposure

被引:81
作者
Fischer, PB
Karlsson, GB
Dwek, RA
Platt, FM
机构
[1] UNIV OXFORD,DEPT BIOCHEM,GLYCOBIOL INST,OXFORD OX1 3QU,ENGLAND
[2] DANA FARBER CANC INST,DIV HUMAN RETROVIROL,BOSTON,MA 02115
基金
英国惠康基金;
关键词
D O I
10.1128/JVI.70.10.7153-7160.1996
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The alpha-glucosidase inhibitor N-butyldeoxynojirimycin (NB-DNJ) is an inhibitor of human immunodeficiency virus (HIV) replication and HIV-induced syncytium formation in vitro. Although an NB-DNJ-mediated change in viral envelope N-glycan composition inhibits HIV entry at the level of post-CD4 binding, the exact mechanism of inhibition remains to be established. In this study we have examined the effects of NB-DNJ on virion envelope composition and CD4-induced gp120 shedding and gp41 exposure. Virion composition analysis revealed an NB-DNJ-mediated reduction of 15% in overall virion envelope glycoprotein content and a reduction of 26% in the proteolytic maturation of virion gp160. Taken together, these two effects resulted in a reduction of approximately 40% in virion gp120 content, CD4-induced shedding of gp120 from the surfaces of envelope-transfected Cos cells was undetectable when gp120 was expressed in the presence of NB-DNJ. Similarly, the shedding of virion-associated gp120 was reduced 7.4-fold, CD4-induced exposure of cryptic gp41 epitopes on the surfaces of HIV-expressing ACH-2 cells was also greatly impaired, and the exposure of virion-associated gp41 epitopes was reduced 4.0-fold, Finally, CD4-induced increases in the binding of antibodies to the V3 loop of ACH-2-cell expressed envelope glycoproteins were reduced 25-fold when the glycoproteins were expressed in the presence of NB-DNJ. These results suggest that the NB-DNJ-mediated retention of glycosylated N-glycans inhibits HIV entry by a combined effect of a reduction in virion gp120 content and a qualitative defect within the remaining gp120, preventing it from undergoing conformational changes after CD4 binding.
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收藏
页码:7153 / 7160
页数:8
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