ANTI-HIV-1 TAT HUMAN SFV INTRABODY GENE THERAPY AGAINST SHIV IN RHESUS MACAQUES

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 HIV-1 感染最常通过性接触获得，全球范围内大多数 HIV-1 性传播都是由于异性接触而发生。 育龄妇女感染 HIV-1 的风险最大，导致全世界妇女、新生儿和婴儿的 HIV-1 感染相应增加。 然而，尽管性传播在 HIV-1 的持续传播中占主导地位，但 HIV-1 向女性的性传播机制仍知之甚少。 例如，尚不清楚无细胞病毒、细胞相关病毒或两者是否对于 HIV-1 在人类中的传播至关重要。 HIV-1跨粘膜上皮传播的潜在机制包括1）上皮细胞的直接感染； 2)通过上皮细胞和/或特化微褶皱(M)细胞的转胞吞作用； 3) 受感染供体细胞的上皮细胞迁移； 4) 摄取上皮内朗格汉斯细胞，5) 通过物理缺口规避上皮屏障。 病毒成功跨越上皮屏障转移可能导致迁移性树突状细胞（通过 DC-SIGN 或另一种甘露糖 C 型凝集素受体）摄取 HIV-1，并随后传播至引流淋巴结和/或局部粘膜 HIV-1 感染，从而招募额外的易感细胞。尽管许多问题仍未得到解答，但这些调查揭示了预防妇女艾滋病毒传播的潜在目标，这对于限制全球艾滋病流行至关重要。 我们建议使用二价人抗 hCXCR4 scFvFc“微型抗体”（框内连接到人 IgG1 Fc（铰链-CH2-CH3）结构域的人单链抗体）来评估治疗性抗体基因转移作为一种新型持久的抗 HIV 杀微生物剂，该抗体可有效抑制 X4 向性 HIV-1 感染并与猕猴 CXCR4 发生交叉反应。 已发表的研究支持这些非致病性病毒进行单次基因转移后至少 4 个月内可以获得高水平的治疗抗体的可能性。 AAV 基因转移载体正在迅速进入其他适应症的高级人体临床试验。 重要的是，一旦分离出这些抗体并完成 HIV/SIV 进入抑制研究，就会对恒河猴交叉反应性抗 CCR5 scFvFc 进行类似的研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. HIV-1 infections are acquired most often through sexual contact, with the majority of the sexual transmission of HIV-1 worldwide occurring as a result of heterosexual contact. Women of childbearing age are at the greatest risk for HIV-1 infection, resulting in a corresponding increase in HIV-1 infection in women, newborns, and infants worldwide. However, despite the predominance of sexual transmission in the continued spread of HIV-1, the mechanisms of sexual transmission of HIV-1 to women are still poorly understood. For example, it is not known whether cell-free virus, cell-associated virus or both are essential for HIV-1 transmission in humans. Potential mechanisms of HIV-1 transmission across mucosal epithelium include 1) direct infection of epithelial cells; 2) transcytosis through epithelial cells and/or specialized microfold (M) cells; 3) epithelial transmigration of infected donor cells; 4) uptake of intraepithelial Langerhans cells and 5) circumvention of the epithelial barrier through physical breaches. Successful transfer of virus across epithelial barriers may result in HIV-1 uptake by migratory dendritic cells (by DC-SIGN or another mannose C-type lectin receptor) and subsequent dissemination to draining lymph nodes and/or localized mucosal HIV-1-infection, leading to recruitment of additional susceptible cells. Although many questions remain unanswered, these investigations have revealed potential targets for prevention of HIV transmission in women which are critical for limiting the global AIDS pandemic. We propose to evaluate therapeutic antibody gene transfer as a novel and durable anti-HIV microbicide using a bivalent human anti-hCXCR4 scFvFc "minibody" (human single-chain antibody linked in frame to the Fc (Hinge-CH2-CH3) domain of human IgG1) that potently inhibits X4-tropic HIV-1 infection and cross-reacts with macaque CXCR4. Published studies support the likelihood that high levels of therapeutic antibodies can be achieved for at least 4 months following a single gene transfer with these non-pathogenic viruses. AAV gene transfer vectors are rapidly moving into advanced stage human clinical trials for other indications. Importantly, similar studies will be performed with rhesus macaque cross-reactive anti-CCR5 scFvFcs as soon as these Abs are isolated and HIV/SIV-entry inhibition studies are completed.