Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
PLoS Pathog. 2011 May;7(5):e1001341. doi: 10.1371/journal.ppat.1001341. Epub 2011 May 12.
A major challenge to developing a successful HIV vaccine is the vast diversity of viral sequences, yet it is generally assumed that an epitope conserved between different strains will be recognised by responding T-cells. We examined whether an invariant HLA-B8 restricted Nef₉₀₋₉₇ epitope FL8 shared between five high titre viruses and eight recombinant vaccinia viruses expressing Nef from different viral isolates (clades A-H) could activate antiviral activity in FL8-specific cytotoxic T-lymphocytes (CTL). Surprisingly, despite epitope conservation, we found that CTL antiviral efficacy is dependent on the infecting viral isolate. Only 23% of Nef proteins, expressed by HIV-1 isolates or as recombinant vaccinia-Nef, were optimally recognised by CTL. Recognition of the HIV-1 isolates by CTL was independent of clade-grouping but correlated with virus-specific polymorphisms in the epitope flanking region, which altered immunoproteasomal cleavage resulting in enhanced or impaired epitope generation. The finding that the majority of virus isolates failed to present this conserved epitope highlights the importance of viral variance in CTL epitope flanking regions on the efficiency of antigen processing, which has been considerably underestimated previously. This has important implications for future vaccine design strategies since efficient presentation of conserved viral epitopes is necessary to promote enhanced anti-viral immune responses.
开发成功的 HIV 疫苗的主要挑战是病毒序列的巨大多样性，但人们普遍认为，不同毒株之间保守的表位将被反应性 T 细胞识别。我们研究了五个高滴度病毒之间共享的 HLA-B8 限制性 Nef₉₀₋₉₇ 不变表位 FL8，以及表达来自不同病毒分离株（A-H 群）的 Nef 的八种重组痘苗病毒，是否能够激活 FL8 特异性细胞毒性 T 淋巴细胞（CTL）的抗病毒活性。令人惊讶的是，尽管存在表位保守性，但我们发现 CTL 的抗病毒功效取决于感染的病毒分离株。只有 23%的 Nef 蛋白，由 HIV-1 分离株或重组痘苗-Nef 表达，被 CTL 最佳识别。CTL 对 HIV-1 分离株的识别与 clade-grouping 无关，但与表位侧翼区的病毒特异性多态性相关，这些多态性改变了免疫蛋白酶体的切割，导致表位生成增强或受损。大多数病毒分离株未能呈现这种保守表位的发现，突出表明 CTL 表位侧翼区病毒变异对抗原加工效率的重要性，这在以前被大大低估了。这对未来的疫苗设计策略具有重要意义，因为有效呈现保守的病毒表位对于促进增强的抗病毒免疫反应是必要的。
