Immune activation promotes evolutionary conservation of T-cell epitopes in HIV-1.
Immune activation promotes evolutionary conservation of T-cell epitopes in HIV-1.
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DOI：
10.1371/journal.pbio.1001523
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发表时间：
2013
期刊：
影响因子：
9.8
通讯作者：
Alcamí J
中科院分区：
文献类型：
--
作者：
Sanjuán R;Nebot MR;Peris JB;Alcamí J
与其他病毒不同，HIV 可能通过保留其 T 细胞表位的序列而受益于免疫识别，从而增强细胞之间的传播。免疫系统应构成强大的选择压力，促进病毒遗传多样性和进化。然而，与其他人类 RNA 病毒相比，HIV 在 T 细胞表位上的序列变异性低于基因组中其他部位的序列变异性。在这里，我们提出表位保守是艾滋病毒和免疫系统之间建立的特定相互作用的结果。一方面，表位识别触发由细胞毒性 T 淋巴细胞 (CTL) 介导的抗 HIV 反应，但另一方面，CD4+ 辅助 T 淋巴细胞 (TH 细胞) 的激活促进 HIV 复制。这些相反选择力的数学模型表明，患者体内水平的选择可以促进 T 细胞表位保存或逃逸。我们预测，当 TH 细胞感染伴随着表位识别（反式感染）时，对总免疫激活水平（免疫优势）有显着贡献的表位会更加保守。我们认为，在疾病的慢性阶段，HIV 驱动的淋巴结免疫激活可能为表位保护提供有利的情况。我们的结果还支持这样的观点，即一些病原体从免疫反应中获益，并表明基于保守 TH 表位的疫苗接种策略可能会适得其反。针对病毒和其他病原体的免疫反应的一个关键组成部分是识别称为表位的短外来蛋白质序列。然而，病毒可以通过突变逃避免疫系统，因此表位应该积累高水平的遗传变异性。这已在几种人类病毒中得到记录，但出乎意料的是，在艾滋病毒中，表位往往相对保守。在这里，我们认为这是艾滋病毒和免疫系统之间发生的特殊相互作用的结果。与其他病毒一样，对 HIV 表位的识别会促进细胞毒性 T 淋巴细胞和辅助 T 淋巴细胞的激活，从而协调细胞免疫反应。然而，HIV 会感染辅助性 T 淋巴细胞作为其体内的靶细胞，并且当这些细胞被激活参与免疫反应时，感染效率会更高。数学模型表明，在某些情况下，艾滋病毒可能会利用免疫激活，从而有利于表位保守。这种情况更有可能发生在触发更强烈 T 细胞反应的表位上，以及在称为“反式感染”的过程中，即辅助 T 淋巴细胞在被激活时被感染。我们的结果强调了基于刺激细胞毒性 T 淋巴细胞而不特异性刺激辅助 T 淋巴细胞的表位的 HIV 疫苗接种策略的潜在优势。
HIV, unlike other viruses, may benefit from immune recognition by preserving the sequence of its T cell epitopes, thereby enhancing transmission between cells. The immune system should constitute a strong selective pressure promoting viral genetic diversity and evolution. However, HIV shows lower sequence variability at T-cell epitopes than elsewhere in the genome, in contrast with other human RNA viruses. Here, we propose that epitope conservation is a consequence of the particular interactions established between HIV and the immune system. On one hand, epitope recognition triggers an anti-HIV response mediated by cytotoxic T-lymphocytes (CTLs), but on the other hand, activation of CD4+ helper T lymphocytes (TH cells) promotes HIV replication. Mathematical modeling of these opposite selective forces revealed that selection at the intrapatient level can promote either T-cell epitope conservation or escape. We predict greater conservation for epitopes contributing significantly to total immune activation levels (immunodominance), and when TH cell infection is concomitant to epitope recognition (trans-infection). We suggest that HIV-driven immune activation in the lymph nodes during the chronic stage of the disease may offer a favorable scenario for epitope conservation. Our results also support the view that some pathogens draw benefits from the immune response and suggest that vaccination strategies based on conserved TH epitopes may be counterproductive. A key component of the immune response against viruses and other pathogens is the recognition of short foreign protein sequences called epitopes. However, viruses can escape the immune system by mutating, so epitopes should accumulate high levels of genetic variability. This has been documented in several human viruses, but in HIV, unexpectedly, epitopes tend to be relatively conserved. Here, we propose that this is a consequence of the peculiar interactions that occur between HIV and the immune system. As with other viruses, recognition of HIV epitopes promotes the activation of cytotoxic and helper T lymphocytes, which then orchestrate a cellular immune response. However, HIV infects helper T lymphocytes as their target cell in the body and does so more efficiently when these cells have been activated to participate in an immune response. Mathematical modeling showed that, in some cases, HIV may take advantage of immune activation, thus favoring epitope conservation. This should be more likely to occur with epitopes that trigger more vigorous T-cell responses, and during the process known as “trans-infection,” in which helper T lymphocytes are infected while being activated. Our results highlight the potential advantages of an HIV vaccination strategy based on epitopes that stimulate cytotoxic T lymphocytes without specifically stimulating helper T lymphocytes.
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影响因子：
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DOI：
10.1073/pnas.0707449104
发表时间：
2007-11-27
影响因子：
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