AN AUTOREGULATED DUAL-FUNCTION ANTITAT GENE FOR HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 GENE-THERAPY

被引:26
作者
LISZIEWICZ, J [1 ]
SUN, D [1 ]
TRAPNELL, B [1 ]
THOMSON, M [1 ]
CHANG, HK [1 ]
ENSOLI, B [1 ]
PENG, B [1 ]
机构
[1] GENET THERAPY INC,GAITHERSBURG,MD 20878
关键词
D O I
10.1128/JVI.69.1.206-212.1995
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
One approach to gene therapy for AIDS is to block the replication of human immunodeficiency virus type 1 (HIV-1) by inhibiting the fat gene, whose product activates the expression of all HIV-1 genes. To accomplish this, we constructed an antitat gene expressing an RNA with dual (polymeric TAR and antisense-tat) function in an attempt to both sequester Tat protein and block its translation from mRNA. A minigene consisting of the antitat gene driven by the HIV-1 long terminal repeat was inserted into a double-copy retrovirus vector, such that antitat expression would be upregulated only in HIV-1-infected cells. After transduction of a T-lymphocytic cell line (Molt-3) the antitat gene inhibited HIV-1 replication. This inhibition was inversely correlated with the virus' infectious dose. Virus replication was also inhibited for 5 months in two different T-cell lines after they had been infected at a high multiplicity of infection, suggesting that the antitat gene may be effective over long periods. Importantly, antitat blocked the replication and the cytopathic effect of HIV-1 in human peripheral blood mononuclear cells and led to as much as 4,000-fold inhibition of the replication of an HIV-1 field isolate as well as HIV-1 prototypes maintained in culture. These results suggest that antitat gene therapy has potential use for blocking HIV-1 replication in infected individuals.
引用
收藏
页码:206 / 212
页数:7
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