Non-Integrating FIV Vectors for HIV Vaccines

用于 HIV 疫苗的非整合 FIV 载体

• 批准号: 7123310
• 负责人: Sybille L Sauter
• 金额: $ 30万
• 依托单位: VIROGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123310
• 关键词: AIDS vaccines; antigens; immune response

DESCRIPTION (provided by applicant): The diagnosis of 15,000 new cases of HIV infections every day demonstrates the pressing need for a prophylactic HIV vaccine to prevent further spread of the pandemic. Some of the most encouraging results have been achieved with viral vector-based vaccines coding for multivalent HIV immunogens. High transduction efficiency of many cell types including dendritic cells as well as in vivo production of immunogens in transduced cells mimic a natural infection without the associated health risks and contribute to the overall efficacy of viral vectors. Since each vector system has certain limitations such as strong anti-vector responses (adeno-, poxviral vectors), limited capacity (AAV), transduction of replicating cells only (retroviral vector) or insertion into the host genome (retro-, lentiviral vectors), we propose to explore a novel non-integrating lentiviral vector based on Feline Immunodeficiency Virus (FIV) which can address these shortcomings of the current vector. So far, the development of lentiviral vectors for HIV vaccines has been hampered by concerns of insertional mutagenesis and general safety for HIV-derived lentiviral vector systems. The proposed FIV vector does not cause disease in humans and does not integrate (FIVdeltaIN), thus avoiding both issues. To date, neither the standard FIV vector nor its integration-deficient version (FIVdeltaIN) have been explored for HIV vaccines. This novel concept combines high transduction efficiency, large payload, weak anti-vector responses allowing repeat vaccinations and the improved safety profile of the feline FIVdeltaIN vector (abolished integration). Here, we propose a proof-of-concept study to demonstrate that non-integrating FIV vectors are capable of inducing immune responses to encoded antigens while avoiding strong anti-vector responses. This hypothesis is based on recent data indicating that genes delivered by integration-deficient lentiviral vectors may be expressed for several days. Additional studies are aimed at investigating humoral and cellular short-term and memory anti-HIV responses of an FIVdeltalN-based HIV vaccine delivering a multivalent HIV-1 immunogen coding for gag, pol, tat and rev. Importantly, adaptive and innate immune responses to the FIVdeltaIN vector will be monitored. In summary, we propose to combine several desirable characteristics within 1 novel viral vector-based delivery system in an effort to address shortcomings of previously described delivery systems for HIV vaccines.

描述（由申请人提供）：每天诊断为15,000例新的HIV感染病例，这表明对预防性HIV疫苗的迫切需要，以防止大流行进一步扩散。基于病毒载体的疫苗编码多价HIV免疫原子，已经实现了一些最令人鼓舞的结果。许多细胞类型的高转导效率，包括树突状细胞以及转导细胞中免疫原的体内产生，模仿自然感染而没有相关的健康风险，并有助于病毒载体的总体功效。 Since each vector system has certain limitations such as strong anti-vector responses (adeno-, poxviral vectors), limited capacity (AAV), transduction of replicating cells only (retroviral vector) or insertion into the host genome (retro-, lentiviral vectors), we propose to explore a novel non-integrating lentiviral vector based on Feline Immunodeficiency Virus (FIV) which可以解决当前向量的这些缺点。到目前为止，由于担心HIV衍生的慢病毒载体系统的插入性诱变和一般安全性，已阻碍了HIV疫苗的慢病毒载体的发展。拟议的FIV载体不会引起人类疾病，也不会整合（fivdeltain），从而避免了这两个问题。迄今为止，尚未针对HIV疫苗探索标准的FIV载体和其集成缺陷版本（Fivdeltain）。这个新颖的概念结合了高转导效率，较大的有效载荷，较弱的抗向量响应，允许重复疫苗接种以及猫科动物fivelterain载体（废除整合）的安全性提高。在这里，我们提出了一项概念验证研究，以证明非整合的FIV载体能够诱导对编码抗原的免疫反应，同时避免强烈的抗载体反应。该假设基于最近的数据，表明通过整合缺陷式慢病毒载体传递的基因可以表达几天。其他研究旨在研究基于Fivdeltaln的HIV疫苗的体液和细胞短期和记忆抗HIV反应，该反应提供多价HIV-1免疫原编码，用于堵嘴，POL，TAT和REV。重要的是，将监测对fivdeltain载体的适应性和先天免疫反应。总而言之，我们建议将几个理想的特征结合在1种新型病毒载体的输送系统中，以解决先前描述的HIV疫苗输送系统的缺点。