Non-Integrating FIV Vectors for HIV Vaccines

说明（由申请人提供）：每天诊断出15 000个新的艾滋病毒感染病例，这表明迫切需要一种预防性艾滋病毒疫苗，以防止这种流行病的进一步蔓延。编码多价艾滋病毒免疫原的基于病毒载体的疫苗取得了一些最令人鼓舞的成果。包括树突状细胞在内的许多细胞类型的高转导效率以及在转导细胞中产生的免疫原模拟了自然感染，而没有相关的健康风险，并有助于病毒载体的整体功效。由于每种载体系统都有一定的局限性，如强抗载体反应（腺病毒载体，痘病毒载体），有限的容量（AAV），只能转导复制细胞（逆转录病毒载体）或插入到宿主基因组（逆转录病毒载体，慢病毒载体），我们提出探索一种新的基于猫免疫缺陷病毒（FIV）的非整合慢病毒载体，可以解决当前载体的这些缺点。到目前为止，HIV疫苗慢病毒载体的开发一直受到插入突变和HIV衍生慢病毒载体系统一般安全性问题的阻碍。提出的FIV载体不会在人类中引起疾病，也不会整合（FIVdeltaIN），从而避免了这两个问题。迄今为止，无论是标准FIV载体还是其整合缺陷版本（FIVdeltaIN）都没有被用于HIV疫苗的研究。这种新概念结合了高转导效率、大载荷、弱抗载体反应，允许重复接种，以及提高猫FIVdeltaIN载体的安全性（取消整合）。在这里，我们提出了一项概念验证研究，以证明非整合FIV载体能够诱导对编码抗原的免疫反应，同时避免强烈的反载体反应。这一假设是基于最近的数据，表明整合缺陷慢病毒载体传递的基因可以表达数天。进一步的研究旨在研究基于fivdeltaln的HIV疫苗的体液和细胞短期和记忆抗HIV反应，该疫苗提供编码gag， pol， tat和rev的多价HIV-1免疫原。重要的是，将监测对FIVdeltaIN载体的适应性和先天免疫反应。总之，我们建议在一个新的基于病毒载体的递送系统中结合几个理想的特性，以努力解决先前描述的HIV疫苗递送系统的缺点。

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.