HIV-1 vector mediated gene therapy for HIV-1 infection

描述（由申请方提供）：本研究的长期目标是 确定基于HIV-I的载体是否可以预防艾滋病疾病进展， 艾滋病毒感染者。我们已经证明，携带抗艾滋病毒的艾滋病毒载体 反义遗传有效负载（VRX 496）可以通过以下途径抑制原代人CD 4 T细胞： 超过90%的转导效率，如两周后通过FACS测量的， 转导以这种方式转导的CD 4 T细胞被直接攻击 与wt-HIV，并显示抑制HIV-I复制在正常的初级CD 4 T细胞 p24的三个对数单位。类似的抑制作用， 当转导的细胞被各种病毒攻击时，观察到wt-HIV复制。 艾滋病毒的主要菌株。值得注意的是，转导有 VRX 496被发现对生产性HIV感染具有抗性，因此， 与未用载体修饰的细胞相比具有存活优势。此外，委员会认为， 初步数据显示，VRX 496在CD 4 T细胞衍生物中具有类似的作用。 来自一个感染艾滋病的捐赠者临床翻译的一个重要目标是 这类载体将表征它们对细胞的抑制作用。 存在于来自HIV感染个体的细胞中的致病性病毒。的 该项目的具体目标是充分表征抑制作用 VRX 496在来源于HIV感染供体的原代人CD 4 T细胞中的表达， 不同的是他们的临床症状。从HIV感染供体中分离的CD 4 T细胞 如果病毒载量、CD 4计数和HAART治疗不一致，则将转导 VRX 496和生物学和抗HIV作用的特点。表征 VRX 496在各种HIV感染的细胞中的作用 离体实验为今后的临床合理设计提供了重要数据， 体内临床研究。 拟议商业应用： 基于HIV-1的载体可以非常高的效率将有效载荷基因递送到原代人类细胞中。当抗HIV有效负载基因被递送到原代CD 4 + T细胞中，然后用wt-HIV感染，病毒复制可以被超过2个对数单位的p24抑制，如通过ELISA抗原捕获测定所测量的。该技术的潜在商业应用之一是治疗艾滋病感染者。该技术也可用于其他疾病的基因治疗，如癌症，因为这类载体可以有效地转染许多细胞类型。

DESCRIPTION (Provided by the applicant): The long-term goal of this study is to determine whether HIV-I based vectors can prevent AIDS disease progression in HIV-infected individuals. We have shown that an HIV vector carrying an anti-HIV antisense genetic payload (VRX496) can transduce primary human CD4 T cells by over 90 percent transduction efficiency, as measured by FACS two weeks after transduction. CD4 T cells transduced in this manner were directly challenged with wt-HIV and shown to inhibit HIV-I replication in normal primary CD4 T cells by over three logarithmic units of p24. Similar inhibitory effects on wt-HIV replication were seen when transduced cells were challenged with various primary strains of HIV. Significantly, primary CD4 T cells transduced with VRX496 were found to be resistant to productive HIV infection and hence, had a survival advantage over cells not modified with the vector. Furthermore, preliminary data have shown similar effects of VRX496 in CD4 T cells derived from one HIV-infected donor. An important goal for the clinical translation of this class of vectors would be to characterize their inhibitory effects on the pathogenic virus present in cells derived from HIV-infected individuals. The specific goal of this project is to fully characterize the inhibitory effects of VRX496 in primary human CD4 T cells derived from HIV-infected donors that differ by their clinical status. CD4 T cells isolated from HIV infected donors discordant in viral load, CD4 count and HAART therapy will be transduced with VRX496 and the biological and anti-HIV effects characterized. Characterization of the effects of VRX496 in the cells from a wide variety of HIV-infected patients ex vivo will provide important data for rational design of future in vivo clinical studies. PROPOSED COMERCIAL APPLICATIONS: HIV-1 based vectors can deliver payload genes into primary human cells with very high efficiency. When a anti-HIV payload gene is deliv ered into primary CD4+ T cells that are then infected with wt-HIV, viral replication can be inhibited by over 2 logarithmic units of p24, as measured by ELISA antigen capture assay. One of the potential commercial applications of the technology is for the treatment of individuals infected with AIDS. The technology can also be used for gene therapy of other diseases such as cancer because this class of vectors can efficiently transduce many cell types.