A Rational Approach for HIV Vaccine T Cell Epitope Selection

描述(申请人提供)：艾滋病毒固有的高变异率创造了足够的序列多样性，对设计通用艾滋病毒疫苗构成了巨大的挑战。自艾滋病毒流行以来的几年里，该病毒成功地利用了许多病毒和宿主途径，避免了免疫识别。最典型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的表位(AE)，其中许多被认为不是免疫原性的，因为这些是CTL逃避的副产品。如果没有恢复的压力，这些人类白细胞抗原-I限制的适应或CTL表位的序列突变似乎会在病毒群体中积累，并随着时间的推移而放大；然而，当传播到不能靶向特定表位的新宿主时，由于病毒适合性的限制，许多很快就会恢复。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人类白细胞抗原-I等位基因，以及迫使病毒回复到不适应状态的病毒适合度限制。我们的初步数据显示，传播的方正病毒(TFV或在新宿主中建立感染的病毒)中的很大比例的CTL表位已经相对于该人的HLA-I(即AE)发生突变，因此不太可能引发有效和广泛的CD8 T细胞反应。此外，我们还有新的数据表明，在急性感染期间传播的适应表位(AE)数量与设定的病毒载量之间存在直接关联。综上所述，这些观察结果突出了一个与艾滋病毒疫苗设计直接相关的真正令人担忧的情景，因为目前所有的艾滋病毒疫苗都编码了大量的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。我们假设其中的大多数将是非适应表位(NAE)，a)将有效地杀死HIV感染的细胞；b)经历CTL逃逸(成为AE)；c)逃逸对病毒造成显著的适应成本；以及d)当免疫压力解除时，NAE恢复到AE。这些特征和在目标1中建议进行评估的附加功能属性将有助于描绘“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，从而否定了对感染疫苗的受试者疾病进展的临床标志物的任何影响。我们还将在候选马赛克疫苗临床试验中评估NAE及其对应的AE的免疫原性。最后，在目标3中，我们通过确定人类白细胞抗原-I结合多肽的结构是否预测免疫反应的质量，获得了关于如何产生最佳CTL反应的机械性见解。总之，这项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的艾滋病毒表位。所获得的信息将对设计和生成衡量未来候选艾滋病毒-1疫苗效力的可评估基准非常有用。

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.