RECOMBINANT CD4-SELECTED HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 VARIANTS WITH REDUCED GP120 AFFINITY FOR CD4 AND INCREASED CELL-FUSION CAPACITY

被引:32
作者
MCKEATING, J [1 ]
BALFE, P [1 ]
CLAPHAM, P [1 ]
WEISS, RA [1 ]
机构
[1] UNIV EDINBURGH,INST ANIM GENET,EDINBURGH EH9 3JN,MIDLOTHIAN,SCOTLAND
关键词
D O I
10.1128/JVI.65.9.4777-4785.1991
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Variants of molecularly cloned human immunodeficiency virus type 1 (HIV-1) were analyzed following selection for the ability to replicate after exposure to soluble, recombinant CD4 protein (rCD4). Two variants, 4/1 and 16/2, show 8-fold and 16-fold reduced sensitivity to rCD4 neutralization yet remain as sensitive as the parental wild-type (wt) virus to neutralization by rCD4-immunoglobulin G (IgG) chimeric molecules and to inhibition of cellular infection by anti-CD4 antibody. The 4/1 variant is more cytopathic, with faster cell fusion and replication kinetics than the wt virus. The gp 120s derived from the 4/1 and 16/2 variants have 3-fold and 30-fold reduced binding affinities to rCD4, respectively. The 4/1 variant exhibits diminished shedding of virion gp 120 induced by rCD4. The binding of and neutralization by V3 loop antibodies and other anti-gp120 antibodies is reduced for 4/1 but not for 16/2. Sequence analysis revealed a codon change at amino acid residue 435 in the C4 region of the gp120 of 16/2. This accounts for its rCD4 insensitivity, since the insertion of this mutation in the wt gp120 yields the same phenotype. The 4/1 variant has a codon change in the V3 region of gp120 (amino acid 311), which accounts for its reduced sensitivity to some neutralizing antibodies but not to rCD4. The ready selection of rCD4-resistant variants has obvious relevance for rCD4-based therapeutic stratagems.
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页码:4777 / 4785
页数:9
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