Long-term inhibition of HIV-1 infection in primary hematopoietic cells by lentiviral vector delivery of a triple combination of anti-HIV shRNA, anti-CCR5 ribozyme, and a nucleolar-localizing TAR decoy
Long-term inhibition of HIV-1 infection in primary hematopoietic cells by lentiviral vector delivery of a triple combination of anti-HIV shRNA, anti-CCR5 ribozyme, and a nucleolar-localizing TAR decoy
复制标题
DOI：
10.1016/j.ymthe.2005.07.524
复制
发表时间：
2005-11-01
影响因子：
12.4
通讯作者：
Rossi, JJ
中科院分区：
文献类型：
--
作者：
Li, MJ;Kim, J;Rossi, JJ
治疗HIV-1感染的组合疗法已被证明可有效降低患者病毒载量并减缓艾滋病的进展。我们已经开发了一系列基于RNA的抑制剂，用于基于基因疗法的HIV-1感染治疗。转录单位已被插入到复制缺陷型慢病毒载体的骨架中，该载体能够转导广泛的细胞类型，包括CD 34（+）造血祖细胞。组合治疗性RNA载体含有靶向HIV-1的rev和达特mRNA的U6 Pol III启动子驱动的短发夹RNA（shRNA）、U6转录的核仁定位TAR RNA诱饵和表达抗CCR 5核酶的VA 1衍生的Pol III盒。这些治疗性RNA中的每一种都靶向不同的基因产物，并通过不同的机制阻断HIV感染。我们的研究结果表明，组合载体抑制HIV复制长期超过加性的方式相对于单一的shRNA或双shRNA/核酶或诱饵组合。我们的数据证明了基于RNA的组合基因疗法治疗HIV-1感染的有效性和有效性。
Combinatorial therapies for the treatment of HIV-1 infection have proven to be effective in reducing patient viral loads and slowing the progression to AIDS. We have developed a series of RNA-based inhibitors for use in a gene therapy-based treatment for HIV-1 infection. The transcriptional units have been inserted into the backbone of a replication-defective lentiviral vector capable of transducing a wide array of cell types, including CD34(+) hematopoietic progenitor cells. The combinatorial therapeutic RNA vector harbors a U6 Pol III promoter-driven short hairpin RNA (shRNA) targeting the rev and tat mRNAs of HIV-1, a U6 transcribed nucleolar-localizing TAR RNA decoy, and a VA1-derived Pol III cassette that expresses an anti-CCR5 ribozyme. Each of these therapeutic RNAs targets a different gene product and blocks HIV infection by a distinct mechanism. Our results demonstrate that the combinatorial vector suppresses HIV replication long term in a more-than-additive fashion relative to the single shRNA or double shRNA/ribozyme or decoy combinations. Our data demonstrate the validity and efficacy of a combinatorial RNA-based gene therapy for the treatment of HIV-1 infection.