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

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH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 中心，不一定是研究者的机构。 HIV-1感染最常通过性接触获得，全世界HIV-1的性传播大多数是异性性接触的结果。 育龄妇女感染HIV-1的风险最大，导致全世界妇女、新生儿和婴儿感染HIV-1的人数相应增加。 然而，尽管性传播在HIV-1的持续传播中占主导地位，但对妇女通过性传播HIV-1的机制仍然知之甚少。 例如，目前尚不清楚无细胞病毒、细胞相关病毒或两者是否是HIV-1在人类中传播所必需的。 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/或特化微折叠（M）细胞的转胞吞作用; 3）受感染供体细胞的上皮迁移; 4）上皮内朗格汉斯细胞的摄取和5）通过物理破坏绕过上皮屏障。 病毒成功转移穿过上皮屏障可能导致HIV-1被迁移性树突状细胞（通过DC-SIGN或另一种甘露糖C型凝集素受体）摄取，随后扩散至引流淋巴结和/或局部粘膜HIV-1感染，导致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，这对限制全球艾滋病流行至关重要。 我们建议使用二价人抗hCXCR 4 scFvFc“minibody”（与人IgG 1的Fc（铰链-CH 2-CH 3）结构域框内连接的人单链抗体）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嗜性HIV-1感染并与猕猴CXCR 4交叉反应。 已发表的研究支持在用这些非致病性病毒进行单次基因转移后至少4个月内可以实现高水平治疗性抗体的可能性。 AAV基因转移载体正在迅速进入其他适应症的高级人类临床试验阶段。 重要的是，一旦这些Ab被分离并且HIV/SIV进入抑制研究完成，将用恒河猴交叉反应性抗CCR 5 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.