Immunogenomics Laboratory, Kirby Institute for Infection and Immunity, University of New South Wales, Sydney, Australia.
School of Medical Sciences, University of New South Wales, Sydney, Australia.
Sci Rep. 2020 Nov 24;10(1):20497. doi: 10.1038/s41598-020-77565-2.
Cytotoxic CD8 T cells are key for immune protection against viral infections. The breadth and cross-reactivity of these responses are important against rapidly mutating RNA viruses, such as dengue (DENV), yet how viral diversity affect T cell responses and their cross-reactivity against multiple variants of the virus remains poorly defined. In this study, an integrated analysis was performed to map experimentally validated CD8 T cell epitopes onto the distribution of DENV genome sequences across the 4 serotypes worldwide. Despite the higher viral diversity observed within HLA-I restricted epitopes, mapping of 609 experimentally validated epitopes sequences on 3985 full-length viral genomes revealed 19 highly conserved epitopes across the four serotypes within the immunogenic regions of NS3, NS4B and NS5. These conserved epitopes were associated with a higher magnitude of IFN-γ response when compared to non-conserved epitopes and were restricted to 13 HLA class I genotypes, hence providing high coverage among human populations. Phylogeographic analyses showed that these epitopes are largely conserved in most of the endemic regions of the world, and with only some of these epitopes presenting distinct mutated variants circulating in South America and Asia.This study provides evidence for the existence of highly immunogenic and conserved epitopes across serotypes, which may impact design of new universal T-cell-inducing vaccine candidates that minimise detrimental effects of viral diversification and at the same time induce responses to a broad human population.
细胞毒性 CD8 T 细胞是针对病毒感染的免疫保护的关键。这些反应的广度和交叉反应性对于快速突变的 RNA 病毒（如登革热病毒[DENV]）很重要，但病毒多样性如何影响 T 细胞反应及其对病毒多种变体的交叉反应性仍未得到明确界定。在这项研究中，对 CD8 T 细胞表位进行了综合分析，以将其映射到全球 4 种血清型的 DENV 基因组序列分布上。尽管在 HLA-I 限制的表位中观察到更高的病毒多样性，但在 3985 个全长病毒基因组上对 609 个经实验验证的表位序列进行映射，揭示了在 NS3、NS4B 和 NS5 的免疫原性区域中，4 种血清型之间存在 19 个高度保守的表位。与非保守表位相比，这些保守表位与 IFN-γ 反应的幅度更高，并且受到 13 种 HLA Ⅰ类基因型的限制，因此在人群中具有高覆盖率。系统发生地理分析表明，这些表位在世界上大多数地方性流行地区都得到了很大程度的保守，而且只有其中一些表位在南美洲和亚洲存在循环的独特突变变体。本研究为跨血清型存在高度免疫原性和保守表位提供了证据，这可能会影响新的通用 T 细胞诱导疫苗候选物的设计，这些候选物可以最小化病毒多样化的不利影响，同时诱导对广泛人群的反应。
