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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 艾滋病毒-1感染最常见的是通过性接触获得的，全世界艾滋病毒-1的大多数性传播是异性接触的结果。育龄妇女感染艾滋病毒-1的风险最大，导致全世界妇女、新生儿和婴儿感染艾滋病毒-1的人数相应增加。然而，尽管性传播在艾滋病毒-1的持续传播中占主导地位，但对艾滋病毒-1通过性传播给妇女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对HIV-1在人类中的传播是必不可少的。HIV-1通过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/或特殊的微折叠(M)细胞的跨细胞作用；3)受感染的供体细胞的上皮移行；4)上皮内朗格汉斯细胞的摄取；5)通过物理破坏绕过上皮屏障。病毒跨上皮屏障的成功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，并随后传播到引流淋巴结和/或局部粘膜HIV-1感染，导致更多易感细胞的招募。尽管许多问题仍未得到回答，但这些调查揭示了预防艾滋病毒在妇女中传播的潜在目标，这对限制全球艾滋病大流行至关重要。 我们建议评价治疗性抗体基因转移作为一种新型和持久的抗HIV微生物剂，使用二价人抗hCXCR4 scFvFc“微体”(与人IgG1的Fc(铰链-CH2-CH3)结构域相连的人单链抗体)，有效地抑制X4嗜性HIV-1感染并与猕猴CXCR4发生交叉反应。已发表的研究支持这样一种可能性，即在用这些非致病病毒进行单一基因转移后，高水平的治疗性抗体至少可以实现4个月。AAV基因转移载体正在迅速进入用于其他适应症的晚期人类临床试验。重要的是，一旦这些抗体被分离出来，并且HIV/SIV进入抑制研究完成，将对恒河猴交叉反应的抗CCR5单链抗体进行类似的研究。

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.