HIGHLY ATTENUATED SIV VIF DNA VACCINES

描述：（改编自申请人的摘要）迫切需要 研制有效和安全的人体免疫机能丧失病毒疫苗 (HIV)其主要目标是阻止艾滋病的蔓延。 在非人灵长类动物中进行的猴免疫缺陷病毒（SIV）和 嵌合病毒（SHIV）已经证明，活的减毒病毒是高度 然而，这些疫苗保持低水平的致病性。我们 一直在研究减毒活猫免疫缺陷病毒（FIV） 诱导猫保护性免疫的疫苗（初步结果）。一 这种疫苗是通过构建具有大的 病毒感染因子（VIF）基因的缺失。在一种新的方法中， 用减毒活病毒疫苗免疫;猫接种 用含有FIV-δ vif前病毒的质粒DNA进行肌内途径 基因组在两个独立的实验中，该疫苗方案在以下方面是有效的： 预防通过肠胃外途径给予的攻击病毒感染。的 目前的拨款计划旨在将这种方法扩展到抗艾滋病疫苗 非人类灵长类动物的发育。因此，我们计划使用SIV感染 恒河猴，以评价减毒活病毒疫苗 这些动物的质粒DNA中含有SIV-δ vif前病毒。因为 大多数艾滋病毒感染是通过粘膜传播的结果， 膜，用这种DNA疫苗接种的猕猴将受到挑战， 通过阴道粘膜给药的毒性病毒。此外，通过建立在 免疫调节剂在病毒免疫中的最新知识，我们将测试关键 细胞因子和趋化因子作为潜在的佐剂通过工程SIV-δ vif前病毒来表达这些免疫调节剂。这种前病毒的DNA形式 表达细胞因子或趋化因子的载体也将接种到 用于在攻击实验中评价的猕猴。因为这个项目将 还对DNA中的抗病毒免疫反应进行了广泛的研究 接种疫苗的动物，可以鉴定免疫相关性， 保护个体免受病毒的粘膜传播。获得的知识 这个关于SIV/猕猴模型的项目将为评估一个 用于预防人类HIV-1感染和艾滋病的DNA疫苗。

DESCRIPTION: (Adapted from Applicant's Abstract) The need is pressing to develop an effective and safe vaccine against the human immunodeficiency virus (HIV) with the primary objective of arresting the spread of the AIDS epidemic. Studies in non-human primates, with simian immunodeficiency virus (SIV) and chimeric virus (SHIV) have demonstrated that live attenuated viruses are highly effective; however, such vaccines maintain a low level of pathogenicity. We have been investigating live-attenuated feline immunodeficiency virus (FIV) vaccines for inducing protective immunity in cats (Preliminary Results). One such vaccine was made by constructing a FIV proviral clone with a large deletion in the viral infectivity factor (vif) gene. In a novel approach to immunization with live attenuated viral vaccines; cats were inoculated by the intramuscular route with plasmid DNA containing the FIV-delta vif proviral genome. In two independent experiments, this vaccine protocol was effective in preventing infection with challenge virus given by the parenteral route. The current grant proposal aims to extend this approach to anti-AIDS vaccine development in non-human primates. Accordingly, we plan to use SIV infection of rhesus macaques to evaluate a live-attenuated viral vaccine by inoculating these animals with plasmid DNA containing an SIV-delta vif provirus. Because the majority of HIV infections are the result of transmission via mucosal membranes, macaques inoculated with this DNA vaccine will be challenged with virulent virus administered via vaginal mucosa. In addition, by building on recent knowledge of immunomodulators in viral immunity, we will test key cytokines and chemokines as potential adjuvants by engineering the SIV-delta vif provirus to express these immunomodulators. The DNA forms of such proviral vectors, expressing cytokines or chemokines, will also be inoculated into macaques for evaluation in challenge experiments. Because this project will also conduct extensive investigations of anti-viral immune responses in DNA vaccinated animals, it may be possible to identify correlates of immunity that protect individuals from mucosal transmission of virus. Knowledge gained in this project on the SIV/macaque model will set the stage for evaluation of a DNA vaccine for preventing HIV-1 infection and AIDS in humans.