Hancock Gemma, Yang Hongbing, Yorke Elisabeth, Wainwright Emma, Bourne Victoria, Frisbee Alyse, Payne Tamika L, Berrong Mark, Ferrari Guido, Chopera Denis, Hanke Tomas, Mothe Beatriz, Brander Christian, McElrath M Juliana, McMichael Andrew, Goonetilleke Nilu, Tomaras Georgia D, Frahm Nicole, Dorrell Lucy
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
Faculty of Medicine, University of Toronto, Toronto, Canada.
PLoS Pathog. 2015 Feb 27;11(2):e1004658. doi: 10.1371/journal.ppat.1004658. eCollection 2015 Feb.
Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called "beneficial" regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control.
确定能够诱导有效CD8+ T细胞反应的HIV免疫原成分对于疫苗开发至关重要。我们通过研究在体外能有效抑制HIV复制的CD8+ T细胞的病毒靶点来解决这个问题，因为这高度预示着体内的病毒控制情况。我们观察到，与未经过挑选的感染HIV的HIV疫苗试验网络（HVTN）参与者相比，病毒血症控制者（VC，病毒载量<5000拷贝/毫升）体内的离体CD8+ T细胞对一组HIV分离株具有广泛而有效的病毒抑制活性。对与进化枝匹配的HIV分离株的病毒抑制作用与靶向Gag、Pol、Nef和Vif中易损区域的CD8+ T细胞频率密切相关，这些易损区域是在一项对近1000名慢性感染个体的独立研究中确定的。这些易损的、即所谓的“有益”区域总体上熵较低，但其中一些区域并未被严格的保守性算法预测到。与此一致的是，在大多数受试者中观察到对与进化枝匹配的病毒的抑制作用强于不匹配的病毒，这表明对进化枝特异性表位的靶向优于保守表位。CD8+ T细胞对有益区域的反应强度，连同病毒熵和HLA I类基因型，解释了高达59%的病毒抑制活性变化，其中T细胞反应强度的独特贡献最为显著。然而，当将编码全长HIV蛋白的疫苗接种到健康志愿者和接受抗逆转录病毒治疗的HIV阳性受试者体内时，有益区域很少被疫苗引发的CD8+ T细胞靶向，这表明免疫优势等级会破坏有效的抗HIV CD8+ T细胞反应。综上所述，我们的数据支持基于系统选择病毒蛋白质组中经验性定义的易损区域、同时排除与HIV控制无关的免疫显性诱饵表位的HIV免疫原设计。
