Analysis of Variant Epitope Specific CD8 T-Cells to Optimize HIV Vaccine Design

描述(由申请人提供)：艾滋病毒疫苗设计领域的一个重大障碍是传播病毒的巨大多样性。突变发生在受感染的受试者体内，然后传播给下一个宿主，这使得制造单一疫苗以防止感染不断进化的病毒的任务变得更具挑战性。在这项应用中，我们试图更好地了解病毒中发生的突变，然后将其传播给另一个人，以及这些突变是否应该成为疫苗的靶标。我们假设，HIV病毒序列中发生并持续存在的一些突变可能能够引发有效的免疫反应，设计识别编码这些突变的病毒的疫苗将是有益的。为了证明这一假设，我们试图评估慢性HIV感染者中CD8T细胞对突变和非突变序列的反应的频率和质量。这些数据将与病毒控制水平进行比较 群体水平，以确定针对突变病毒的免疫反应对病毒复制的贡献。每个表位的分数将根据一系列特征进行计算，得分高的表位是疫苗纳入的理想选择。在第二个目标中，我们将对初次感染HIV的病毒进行测序，以确定单个感染病毒株编码的突变和非突变序列的频率。然后，我们将检查针对突变或非突变序列的CD8T细胞的频率和质量。我们希望发现，针对一些突变的序列将是有益的，而其他序列将引起较差的质量或根本没有反应。这些结果将通过定义要靶向或排除的特定病毒序列来指导未来疫苗的设计。最后，在最后一个目标中，我们将评估马赛克疫苗引发识别突变病毒的免疫反应的能力。马赛克疫苗的设计是具有编码非突变和常见突变的病毒序列，以增加在接种者中引发的免疫反应的数量。我们将列举作为该疫苗构建的结果而产生的反应的频率和质量。综上所述，这项提议将确定在艾滋病毒感染和疫苗接种的背景下识别突变病毒的免疫反应的生物学意义。这些信息将对未来的HIV-1疫苗设计和有效性测试具有极其重要的意义。

DESCRIPTION (provided by applicant): A significant hurdle in the field of HIV vaccine design is the enormous diversity of the circulating virus. Mutations occur within an infected subject and are then transmitted to the next host making the task of generating a single vaccine that prevents infection from an ever-evolving virus more challenging. In this application, we seek to have a better understanding of the mutations occurring in the virus that are then transmitted to another individual and whether or not these mutations should be targeted by a vaccine. We hypothesize that some mutations that occur and persist in the viral sequence of HIV may be able to elicit an effective immune response and that designing vaccines to recognize virus encoding these mutations will be beneficial. To prove this hypothesis, we seek to evaluate the frequency and quality of CD8 T cell responses to mutated and non-mutated sequences in chronically HIV infected subjects. These data will be compared with the level of viral control at a population level to determine the contribution of immune responses targeting mutated virus to viral replication. A score for each epitope will be calculated based a number of characteristics with high scoring epitopes being ideal for vaccine inclusion. In the second aim, we will sequence the virus in primary HIV infection to determine the frequency of mutated and non-mutated sequences encoded by the single infecting viral strain. We will then examine the frequency and quality of CD8 T cells targeting the mutated or nonmutated sequences. We expect to find that targeting some mutated sequences will be beneficial while other sequences will elicit poor quality or no response at all. These results will inform the design of future vaccines by defining specific viral sequences to target or exclude. Finally, in the last aim, we will evaluate the capacity of a mosaic vaccine to elicit immune responses that recognize mutated virus. Mosaic vaccines are designed to have viral sequences that encode non-mutated and common mutants to increase the number of immune responses elicited in the vaccinee. We will enumerate the frequency and determine the quality of the responses generated as a result of this vaccine construct. Taken together, this proposal will determine the biologic significance of immune responses recognizing mutated virus in context of HIV infection and vaccination. Such information will be extremely pertinent for future HIV-1 vaccine design and efficacy testing.