Single-Cycle SIV as a Novel AIDS Vaccine Approach

描述（由申请人提供）：在正在进行的临床试验中，基于重组载体的艾滋病候选疫苗可能最终无法提供针对HIV-1的充分保护。减毒活疫苗在动物中提供更可靠的保护，但在可预见的未来，对其安全性的合理担忧可能会阻止其在人类中的使用。 因此，继续寻找一种既安全又有效的艾滋病疫苗。一种有希望的方法是使用仅限于单个感染周期的慢病毒。我们已经开发了一种独特的系统，用于生产SIV菌株，该系统作为非复制型疫苗方法仅限于一轮感染。被这种单周期SIV（scSIV）感染的细胞表达除Pol之外的所有病毒基因产物，并释放不能完成随后几轮感染的未成熟病毒颗粒。在初步研究中，用scSIV免疫的恒河猴对多种病毒抗原产生抗体和T细胞应答。在用SIVmac 239（一种众所周知难以通过疫苗接种保护的毒株）静脉内攻击后，这些动物相对于未接种疫苗的对照动物也表现出急性和慢性期病毒载量的显著降低。我们现在建议更全面地评估这种新型疫苗方法可能达到的保护程度。在具体目标1中，我们将测试两种不同的scSIV疫苗方案，以比较接种频率与剂量对病毒特异性免疫应答的发展以及致病性SIV攻击后遏制感染的能力的影响。在具体目标2中，我们将检验以下假设：由scSIV的病毒修饰株诱导中和抗体可以增强保护。在具体目标3中，我们将确定scSIV免疫的位点是否影响病毒特异性T细胞应答的粘膜归巢性质和保护免受粘膜SIV攻击的能力。将针对每个特定目的分析scSIV引发的免疫应答与攻击结果之间的关联，以揭示潜在的保护机制。

DESCRIPTION (provided by applicant): AIDS vaccine candidates based on recombinant vectors may ultimately fail to provide adequate protection against HIV-1 in ongoing clinical trials. Live, attenuated vaccines afford more reliable protection in animals, but justifiable concerns about their safety will likely preclude their use in humans for the foreseeable future. Thus, the search continues for an AIDS vaccine that optimizes both safety and efficacy. One promising approach is the use of lentiviruses that are limited to a single cycle of infection. We have developed a unique system for producing strains of SIV that are limited to one round of infection as a non-replicating vaccine approach. Cells infected with this single-cycle SIV (scSIV) express all of the viral gene products except for Pol and release immature virus particles that cannot complete subsequent rounds of infection. In preliminary studies, rhesus macaques immunized with scSIV made antibody and T cell responses to multiple viral antigens. Following an intravenous challenge with SIVmac239, a strain that is notoriously difficult to protect against by vaccination, these animals also exhibited significant reductions in both acute and chronic phase viral loads relative to unvaccinated control animals. We now propose to more fully evaluate the extent of protection that may be achieved by this novel vaccine approach. In specific aim 1, we will test two different scSIV vaccine regimens to compare the effects of frequency versus dose of inoculation on the development of virus-specific immune responses and the ability to contain infection after a pathogenic SIV challenge. In specific aim 2, we will test the hypothesis that the induction of neutralizing antibodies by envelope-modified strains of scSIV can enhance protection. In specific aim 3, we will determine if the site of scSIV immunization influences the mucosal homing properties of virus-specific T cell responses and the ability to protect against a mucosal SIV challenge. Associations between immune responses elicited by scSIV and the outcome of challenge will be analyzed for each specific aim to reveal potential mechanisms of protection.