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。突变发生在被感染者体内，然后传播给下一个宿主，这使得制造一种单一疫苗以防止感染不断进化的病毒的任务更具挑战性。在这项应用中，我们试图更好地了解病毒中发生的突变，然后传播给另一个人，以及这些突变是否应该被疫苗靶向。我们假设，在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，并且设计出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感染受试者中CD8 T细胞对突变和非突变序列反应的频率和质量。这些数据将与a的病毒控制水平进行比较

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.