Mapping HIV-1 vaccine induced T-cell responses: bias towards less-conserved regions and potential impact on vaccine efficacy in the Step study.
Mapping HIV-1 vaccine induced T-cell responses: bias towards less-conserved regions and potential impact on vaccine efficacy in the Step study.
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DOI：
10.1371/journal.pone.0020479
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Self SG
中科院分区：
文献类型：
--
作者：
Li F;Finnefrock AC;Dubey SA;Korber BT;Szinger J;Cole S;McElrath MJ;Shiver JW;Casimiro DR;Corey L;Self SG
T细胞定向的HIV疫苗基于诱导CD 8 + T细胞记忆应答，其将有效抑制感染HIV-1毒株的感染和随后的复制，这是一个需要疫苗接种诱导的表位与感染病毒毒株之间匹配或接近匹配的过程。我们比较了在Step试验中使用的复制缺陷型Ad 5 gag/pol/nef疫苗引起的CTL表位应答的频率和特异性，以及在最近测序的HIV-1进化枝B分离株中遇到这些表位的可能性。在具有可检测的15-mer肽库ELISpot应答的疫苗接种者中，通过9-mer肽ELISpot测定法检测到每个疫苗接种者有四个（一个Gag、一个Nef和两个Pol）CD 8表位的中值。重要的是，频率分析的映射表位表明，有一个显着的倾斜的T细胞反应，可变表位检测更频繁地比预期从一个公正的抽样的疫苗序列。相应地，Gag、Pol和Nef中最高度保守的表位（通过在Los Alamos数据库www.hiv.lanl.gov中当前>80%的序列中存在来定义）以低于无偏采样的频率检测到，类似于针对对自然感染的应答所报道的频率，表明这些应答的潜在表位掩蔽。这可能是病毒在两种情况下逃避有效的T细胞免疫监视的通用机制。Step试验令人失望的结果提高了未来HIV疫苗候选者的标准。本报告强调了Step试验中使用的相同疫苗中存在的保守性较低的表位的偏倚。开发可以引起更广泛的反应的疫苗策略，特别是针对基因组的保守区域，是针对HIV-1的有效T细胞疫苗的关键要求。ClinicalTrials.gov NCT 00849680，MRKAd 5 Gag/Pol/Nef疫苗在健康成人中的安全性、耐受性和免疫原性研究。
T cell directed HIV vaccines are based upon the induction of CD8+ T cell memory responses that would be effective in inhibiting infection and subsequent replication of an infecting HIV-1 strain, a process that requires a match or near-match between the epitope induced by vaccination and the infecting viral strain. We compared the frequency and specificity of the CTL epitope responses elicited by the replication-defective Ad5 gag/pol/nef vaccine used in the Step trial with the likelihood of encountering those epitopes among recently sequenced Clade B isolates of HIV-1. Among vaccinees with detectable 15-mer peptide pool ELISpot responses, there was a median of four (one Gag, one Nef and two Pol) CD8 epitopes per vaccinee detected by 9-mer peptide ELISpot assay. Importantly, frequency analysis of the mapped epitopes indicated that there was a significant skewing of the T cell response; variable epitopes were detected more frequently than would be expected from an unbiased sampling of the vaccine sequences. Correspondingly, the most highly conserved epitopes in Gag, Pol, and Nef (defined by presence in >80% of sequences currently in the Los Alamos database www.hiv.lanl.gov) were detected at a lower frequency than unbiased sampling, similar to the frequency reported for responses to natural infection, suggesting potential epitope masking of these responses. This may be a generic mechanism used by the virus in both contexts to escape effective T cell immune surveillance. The disappointing results of the Step trial raise the bar for future HIV vaccine candidates. This report highlights the bias towards less-conserved epitopes present in the same vaccine used in the Step trial. Development of vaccine strategies that can elicit a greater breadth of responses, and towards conserved regions of the genome in particular, are critical requirements for effective T-cell based vaccines against HIV-1. ClinicalTrials.gov NCT00849680, A Study of Safety, Tolerability, and Immunogenicity of the MRKAd5 Gag/Pol/Nef Vaccine in Healthy Adults.
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作者：
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