A NOVEL, LOGICAL APPROACH TO HIV VACCINE DEVELOPMENT

描述：(改编自申请者摘要)我们将从根本上追求 不同的艾滋病毒疫苗设计方法。艾滋病毒感染者的治疗 单一的抗逆转录病毒药物往往会导致变异的出现， 抗药性病毒。我们最近发现，细胞免疫反应 对病毒施加类似的选择性压力。我们将设计候选人 通过识别病毒在高度选择性作用下的那些区域来接种疫苗 在急性SIV感染期间的压力。我们会在4点对整个病毒进行测序 感染后16周，以确定细胞免疫反应 在控制早期病毒复制方面很重要。我们的假设是 疫苗诱导施加选择性压力的细胞毒性T淋巴细胞(CTL) 将减少猕猴体内最初的病毒复制 SIV。为了解决这个假设，我们首先需要知道CTL中的哪一个 反应控制病毒复制。在特定的目标I中，我们将对 12只猕猴在感染后2、4和16周的SIV病毒全基因组 用分子克隆病毒来识别病毒的区域，这些区域 逃走了。我们将使用一组重叠的多肽跨越整个 SIVmac239基因组在这些感染动物中的细胞免疫反应图谱 使用ELISPOT分析。在特定的目标IIwe然后将接种猕猴疫苗 通过免疫反应逃脱识别的病毒区域。我们 已经有初步数据表明病毒分离了4周 感染后“逃脱”了强烈的CTL反应。这表明， 负责选择逃逸变异体的CTL摧毁了所有细胞 积极生产野生型病毒。因此，我们将在 在急性感染期间逃逸以诱导强大的CTL的野生型病毒。我们 预测这些疫苗诱导的CTL反应将减少最初的 病毒血症，并防止逃逸突变的产生，从而促进 发展强烈的宿主免疫反应。这项提议的结果是 利用被SIV挑战的恒河猴将直接与 HIV疫苗的合理设计。如果用病毒的区域接种疫苗 在急性期逃脱可以减少猕猴最初的病毒血症，然后我们 可以在疫苗接种方案中使用艾滋病毒中的类似区域。事实上，CTL 基于表位的疫苗已经在牛津和肯尼亚处于第一阶段试验 麦克迈克尔博士的方向。因此，我们的研究结果将是 在这种疫苗的最终设计中很重要。

DESCRIPTION: (Adapted from Applicant's Abstract) We will pursue a radically different approach to HIV vaccine design. Treatment of HIV-infected patients with single antiretroviral drugs often results in the emergence of variant, drug-resistant viruses. We have recently shown that cellular immune responses place similar selective pressure on the virus. We will design candidate vaccines by identifying those regions of the virus under intense selective pressure during acute SIV infection. We will sequence the entire virus at 4 and 16 weeks post-infection to determine cellular immune responses that are important in controlling early viral replication. Our hypothesis is that vaccine-induction of cytotoxic T lymphocyte (CTL) that exert selective pressure on the virus will reduce initial virus replication in macaques challenged with SIV. To address this hypothesis we first need to know which of the CTL responses control virus replication. In Specific Aim I we will sequence the entire SIV viral genome from 12 macaques at 2, 4 and 16 weeks post-infection with a molecularly cloned virus to identify regions of the virus, which have escaped. We will use an overlapping set of peptides spanning the entire SIVmac239 genome to map cellular immune responsesin these infected animals using ELISPOT assays. In Specific Aim IIwe will then vaccinate macaqueswith the regions of the virus that have escaped recognition by the immune response. We already have preliminary data suggesting that virus isolated 4 weeks post-infection has "escaped" from a strong CTL response. This suggests that the CTL responsible for selecting the escape variants had destroyed all cells actively producing the wild-type virus. We will, therefore, use epitopes in the wild-type virus that escape during acute infection to induce robust CTL. We predict that these vaccine-induced CTL responses will reduce the initial viremia, and prevent escape mutant generation, thereby facilitating the development of strong host immune responses. The results of this proposal utilizing rhesus macaques challenged with SIV will have direct relevance to the rational design of a vaccine for HIV. If vaccination with regions of the virus that escape during the acute phase reduce initial viremia in macaques, then we can use analogous regions in HIV in vaccination regimens. Indeed, a CTL epitope-based vaccine is already in Phase I trials in Oxford and Kenya under the direction of Dr. McMichael. Thus, results from our studies will be important in the eventual design of this vaccine.