Combination genetic therapy to inhibit HIV-1.
Combination genetic therapy to inhibit HIV-1.
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抑制 HIV-1 的联合基因疗法。
DOI：
10.1006/mthe.2001.0513
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Pomerantz,RogerJ
中科院分区：
文献类型：
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作者：
Strayer,DavidS;Branco,Francisco;Landré,Julien;BouHamdan,Mohamad;Shaheen,Farida;Pomerantz,RogerJ
与单一药物相比，联合抗慢病毒药物治疗同时靶向多种HIV-1功能，最大限度地提高疗效并降低逃逸突变的机会。联合基因治疗理论上可以提高疗效，但即使是单一基因的交付高百分比的造血细胞或其衍生物已被证明是有问题的。由于它们的基因递送效率高，我们为此目的测试了重组SV 40衍生载体（rSV 40）。我们制造了6个rSV 40，每个都携带不同的转基因，靶向不同的慢病毒功能。我们测试了这些构建体单独以及双重和三重组合保护SupT 1人类T淋巴瘤细胞免受HIV-1攻击的能力。使用抗CXCR 4和抗HIV-1逆转录酶（RT）和整合酶（IN）的单链抗体（SFv），以及聚合物TAR诱饵（PolyTAR）和HIV-1 Rev的显性阴性突变体（RevM 10）。免疫染色显示，几乎所有的双重处理的细胞表达两种转基因。所有转基因都能单独保护HIV-1，但除抗CXCR 4 SFv外，其有效性随着攻击剂量从40增加到2500组织培养感染剂量50（TCID 50）/106个细胞而降低。然而，所有转基因组合都比单个转基因更好地保护靶细胞，即使是最高的攻击剂量。因此，联合基因疗法可能比单一药物更好地抑制HIV-1，并且rSV 40可能有助于多基因疗法的递送。
Compared with single agents, combination antilentiviral pharmacotherapy targets multiple HIV-1 functions simultaneously, maximizing efficacy and decreasing chances of escape mutations. Combination genetic therapy could theoretically enhance efficacy similarly, but delivery of even single genes to high percentages of hematopoietic cells or their derivatives has proven problematic. Because of their high efficiency of gene delivery, we tested recombinant SV40-derived vectors (rSV40s) for this purpose. We made six rSV40s, each carrying a different transgene that targeted a different lentiviral function. We tested the ability of these constructs, individually and in double and triple combinations, to protect SupT1 human T lymphoma cells from HIV-1 challenge. Single chain antibodies (SFv) against CXCR4 and against HIV-1 reverse transcriptase (RT) and integrase (IN) were used, as were polymeric TAR decoys (PolyTAR) and a dominant-negative mutant of HIV-1 Rev (RevM10). Immunostaining showed that virtually all doubly treated cells expressed both transgenes. All transgenes individually protected from HIV-1 but, except for anti-CXCR4 SFv, their effectiveness diminished as challenge doses increased from 40 through 2500 tissue culture infectious dose50(TCID50)/106cells. However, all combinations of transgenes protected target cells better than individual transgenes, even from the highest challenge doses. Thus, combination gene therapies may inhibit HIV-1 better than single agents, and rSV40s may facilitate delivery of multigene therapeutics.