A Rational Approach for HIV Vaccine T Cell Epitope Selection

描述（由申请人提供）：HIV固有的高突变率创造了足够的序列多样性，对设计通用HIV疫苗构成了巨大的挑战。自艾滋病毒开始流行以来，多年来，该病毒成功地利用了许多病毒和宿主途径来避免免疫识别。最具特征和最常见的病毒适应之一是逃避细胞毒性T淋巴细胞（CTL）。这种逃避方法产生适应性表位（AE），其中许多表位预计不会具有免疫原性，因为它们是CTL逃逸的副产物。这些hla - 1限制性适应或CTL表位序列突变似乎在病毒群体中积累，并随着时间的推移而扩大，如果没有恢复的压力；然而，许多病毒在传播到不能靶向特定表位的新宿主时，由于病毒适应性限制而迅速恢复。因此，一个群体中病毒的组成是不断变化的，这取决于该群体中驱动逃逸的hla - 1等位基因和迫使病毒恢复到非适应状态的病毒适应度约束。我们的初步数据显示，在传播的创始人病毒（TFV或在新宿主中建立感染的病毒）中，很大一部分CTL表位已经与患者的hla - 1（即AE）发生了突变，因此不太可能引发有效和广泛的CD8 t细胞反应。此外，我们也有初步数据表明急性感染期间传播的适应表位（AE）数量与设定点病毒载量之间存在直接相关性。综上所述，这些观察结果突出了一个与HIV疫苗设计直接相关的真正令人担忧的情况，因为目前所有HIV疫苗都编码大量AE。为了解决这个问题，我们将首先确定HIV特异性CTL表位，这些表位将非常值得纳入未来的候选HIV免疫原中。我们假设其中大部分将是非适应性表位（NAE），它们a)将有效地杀死HIV感染的细胞；b)发生CTL逃逸（成为AE）；C)病毒的逃逸造成了巨大的适应成本；d)免疫压力解除后，NAE恢复为AE。这些特征和额外的功能属性将有助于描述“最佳CTL表位”的特征。目的2将确定在先前的疗效研究中使用的疫苗是否富含AE，从而对感染的疫苗接种者疾病进展的临床标志物没有任何影响。我们还将在候选花叶疫苗临床试验中评估NAE及其AE对应物的免疫原性。最后，在目标3中，我们通过确定hla - 1结合肽的结构是否预测免疫反应的质量，获得了如何产生最佳CTL反应的机制见解。总之，该提案将在急性感染和疫苗接种的背景下定义重要的非适应和适应HIV表位。所获得的信息对于设计和产生衡量未来候选艾滋病毒-1疫苗效力的可评估基准将非常有用。

DESCRIPTION (provided by applicant): The high mutation rates inherent to HIV have created sufficient sequence diversity to pose a formidable challenge in designing a universal HIV vaccine. Over the years since the start of the HIV epidemic, the virus has successfully utilized many viral and host pathways to avoid immune recognition. One of the best-characterized and most frequent viral adaptations is escape from cytotoxic T lymphocyte (CTL). This evasion method generates adapted epitopes (AE) many of which are not expected to be immunogenic since these are by-products of the CTL escape. These HLA-I restricted adaptations or sequence mutations in CTL epitopes appear to accumulate in a viral population and amplify over time if there is no pressure to revert; however, many revert rapidly due to viral fitness constraints when transmitted to new hosts who cannot target the specific epitope. The make up of a virus in a population is therefore in constant flux depending on the HLA-I alleles in that population driving escape and viral fitness constraints that force reversions back to its non- adapted state. Our preliminary data shows that a large proportion of CTL epitopes in a transmitted founder virus (TFV or virus that established infection in a new host) are already mutated with respect to that person's HLA-I (i.e. AE) making it unlikely that an effective and broad CD8 T-cell response will be elicited. In addition, we also have nascent data demonstrating a direct correlation between number of adapted epitopes (AE) transmitted during acute infection and set point viral load. Taken together, these observations highlight a truly concerning scenario pertinent directly to HIV vaccine design since all current HIV vaccines encode a large number of AE. To address this problem, we will first identify HIV specific CTL epitopes that would strongly merit inclusion n future candidate HIV immunogens. We hypothesize that a majority of these will be the non-adapted epitopes (NAE) which a) will effectively kill HIV infected cells; b) undergo CTL escape (to become AE); c) the escape inflicting a significant fitness cost to the virus; and d) the NAE reverts to AE when the immune pressure is lifted. These features and additional functional attributes proposed for evaluation in aim 1 will help delineate a signature for "optimal CTL epitopes". Aim 2 will determine whether vaccines, used in prior efficacy studies, were enriched in AE thereby negating any effect on clinical markers of disease progression in vaccinees who became infected. We will also evaluate the immunogenicity of NAE and their AE counterparts in a candidate mosaic vaccine clinical trial. Finally, in aim 3 we gain mechanistic insights into how optimal CTL responses are generated by determining whether the structure of HLA-I bound peptides predicts the quality of the immune response. In summary, this proposal will define important non-adapted and adapted HIV epitopes in context of acute infection and vaccination. The information obtained will be immensely useful both for the design and generation of an evaluable benchmark for gauging the efficacy of future candidate HIV-1 vaccines.