The antiviral efficacy of HIV-specific CD8⁺ T-cells to a conserved epitope is heavily dependent on the infecting HIV-1 isolate.
The antiviral efficacy of HIV-specific CD8⁺ T-cells to a conserved epitope is heavily dependent on the infecting HIV-1 isolate.
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DOI：
10.1371/journal.ppat.1001341
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发表时间：
2011-05
期刊：
影响因子：
6.7
通讯作者：
Dong T
中科院分区：
文献类型：
--
作者：
Ranasinghe SR;Kramer HB;Wright C;Kessler BM;di Gleria K;Zhang Y;Gillespie GM;Blais ME;Culshaw A;Pichulik T;Simmons A;Rowland-Jones SL;McMichael AJ;Dong T
开发成功的HIV疫苗的一个主要挑战是病毒序列的巨大多样性，但通常认为不同毒株之间保守的表位将被应答T细胞识别。我们研究了在5种高滴度病毒和8种表达来自不同病毒分离株（进化枝A-H）的Nef的重组牛痘病毒之间共享的恒定HLA-B8限制性Nef 90 -97表位FL 8是否可以激活FL 8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，尽管表位保守，我们发现CTL抗病毒功效依赖于感染的病毒分离株。只有23%的Nef蛋白，表达的HIV-1分离株或重组疫苗Nef，最佳识别的CTL。CTL对HIV-1分离株的识别独立于分支分组，但与表位侧翼区的病毒特异性多态性相关，这改变了免疫蛋白酶体切割，导致表位产生增强或受损。大多数病毒分离株未能呈现这种保守表位的发现突出了CTL表位侧翼区中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，因为保守病毒表位的有效呈递对于促进增强的抗病毒免疫应答是必要的。开发有效的HIV疫苗的最大挑战之一是HIV快速改变其病毒序列的能力。病毒序列的这种变异使病毒能够经常逃避宿主免疫系统的识别。为了解决这个问题，人们越来越关注开发针对HIV毒株之间高度保守的病毒区域的T细胞应答的HIV疫苗。然而，以前的研究主要集中在识别单个病毒分离株内的氨基酸变异，或者集中在经典的表位内逃逸突变。我们的研究评估了T细胞识别共有13个HIV毒株的保守表位。引人注目的是，我们发现只有一小部分病毒株被T细胞有效识别和靶向。相比之下，在大多数测试的HIV毒株中，表位侧翼区域中的氨基酸序列差异损害了表位的细胞内加工和呈递。因此，我们的研究结果强调，尽管绝对表位保守，但很大比例的HIV毒株可能会逃避表位特异性T细胞识别。这对疫苗设计和疫苗效力的评价都具有重要意义。
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. One of the greatest challenges to developing an effective HIV vaccine is the ability of HIV to rapidly alter its viral sequence. Such variation in viral sequence enables the virus to frequently evade recognition by the host immune system. To counteract this problem, there has been increasing interest in developing HIV vaccines that target T-cell responses to the regions of the virus that are highly conserved between strains of HIV. However, previous studies have focused on identifying amino acid variation predominantly within a single viral isolate, or have focused on classical within-epitope escape mutation. Our study assessed T-cell recognition of a conserved epitope shared by a total of 13 HIV strains. Strikingly, we show that only a small proportion of the viral strains were effectively recognised and targeted by the T-cells. In contrast, differences in amino acid sequence in the region flanking the epitope impaired the intracellular processing and presentation of epitope in the majority of HIV strains tested. Thus, our findings highlight that a large proportion of HIV strains may evade epitope-specific T-cell recognition despite absolute epitope conservation. This has important implications for both vaccine design and evaluation of vaccine efficacy.
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