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

抗 HIV-1 TAT 人类 SFV 体内针对恒河猴 SHIV 的基因治疗

• 批准号: 8172807
• 负责人: Wayne A. Marasco
• 金额: $ 6.58万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172807
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Antibodies; C Type Lectin Receptors; CD209 gene; CXCR4 gene; Cells; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Cross Infection; Dendritic Cells; Epithelial; Epithelial Cells; Epithelium; Female of child bearing age; Funding; Gene Transfer; Grant; HIV-1; Heterosexuals; Human; IgG1; Infection; Institution; Investigation; Langerhans cell; Link; M cell; Macaca; Macaca mulatta; Mannose; Newborn Infant; Publishing; Research; Research Personnel; Resources; Risk; Satellite Viruses; Sexual Transmission; Source; Staging; Therapeutic antibodies; United States National Institutes of Health; Virus; Woman; anti-HIV microbicide; gene therapy; gene transfer vector; intraepithelial; lymph nodes; novel; pandemic disease; transcytosis; transmission process; uptake

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 HIV-1感染最常通过性接触获得，大部分是由于异性恋接触而发生的HIV-1性传播。 生育年龄的妇女患HIV-1感染的风险最大，导致全世界女性，新生儿和婴儿的HIV-1感染相应增加。 然而，尽管HIV-1继续传播性传播的性传播占主导地位，但HIV-1向女性的性传播机制仍然很少了解。 例如，尚不清楚无细胞病毒，与细胞相关的病毒或两者都是人类HIV-1传播至关重要的。 HIV-1跨粘膜上皮的潜在机制包括1）直接感染上皮细胞； 2）通过上皮细胞和/或专门的微膜（M）细胞的转胞细胞增多； 3）受感染供体细胞的上皮转移； 4）摄取上皮内兰格汉细胞和5）通过物理漏洞规避上皮屏障。 成功地在上皮屏障中转移了病毒可能会导致迁移的树突状细胞（通过DC-SIGN或其他甘露糖C型凝集素受体）的HIV-1摄取，然后随后传播淋巴结和/或局部粘膜HIV HIV-1感染，从而导致其他可感染细胞的募集。尽管许多问题仍未得到解决，但这些调查揭示了预防女性预防艾滋病毒传播的潜在目标，这对于限制全球艾滋病大流行至关重要。 我们建议使用双价性人类抗HCXCR4 SCFVFC“ MiniBoty”（在框架中链接到FC（HINGE-CH2-CH3）框架（hinge-CH2-CH3）域的人类IGG1的X4-1-1-1-1-1-1-1-1- CXCR4。 已发表的研究支持在单个基因转移使用这些非致病性病毒后至少4个月实现高水平的治疗性抗体的可能性。 AAV基因转移载体正在迅速进入先进的人类临床试验，以获取其他适应症。 重要的是，一旦分离出这些ABS，将对恒河猴交叉反应抗CCR5 SCFVFC进行类似的研究，并完成HIV/SIV抑制研究。