Non-Integrating FIV Vectors for HIV Vaccines

描述（由申请人提供）：每天诊断出15，000例新的艾滋病毒感染病例，表明迫切需要预防性艾滋病毒疫苗，以防止大流行病的进一步传播。一些最令人鼓舞的结果已经取得了与病毒载体为基础的疫苗编码的多价艾滋病毒免疫原。包括树突状细胞在内的许多细胞类型的高转导效率以及转导细胞中免疫原的体内产生模拟自然感染，而没有相关的健康风险，并有助于病毒载体的总体功效。由于每个载体系统都有一定的局限性，如强的抗载体反应（腺病毒，痘病毒载体），有限的能力（AAV），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，慢病毒载体），我们建议探索一种新的非整合的慢病毒载体的基础上猫免疫缺陷病毒（FIV），可以解决目前的载体的这些缺点。到目前为止，用于HIV疫苗的慢病毒载体的开发受到了对插入诱变和HIV衍生的慢病毒载体系统的一般安全性的担忧的阻碍。所提出的FIV载体不会在人类中引起疾病并且不会整合（FIVdeltaIN），因此避免了这两个问题。迄今为止，标准FIV载体及其整合缺陷型（FIVdeltaIN）均未用于HIV疫苗。这种新概念结合了高转导效率、大有效负载、允许重复疫苗接种的弱抗载体反应以及猫FIVdeltaIN载体的改善的安全性特征（消除整合）。在这里，我们提出了一个概念验证的研究，以证明非整合FIV载体能够诱导免疫反应的编码抗原，同时避免强烈的抗载体反应。这一假设是基于最近的数据表明，基因传递的整合缺陷型慢病毒载体可以表达几天。其他研究旨在调查基于FIVdeltaIN的HIV疫苗的体液和细胞短期和记忆抗HIV应答，所述基于FIVdeltaIN的HIV疫苗递送编码gag、pol、达特和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性免疫应答。总之，我们提出将联合收割机几个期望的特征结合在一个新的基于病毒载体的递送系统中，以努力解决先前描述的用于HIV疫苗的递送系统的缺点。

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.