High-avidity, high-IFNγ-producing CD8 T-cell responses following immune selection during HIV-1 infection
High-avidity, high-IFNγ-producing CD8 T-cell responses following immune selection during HIV-1 infection
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DOI：
10.1038/icb.2011.34
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发表时间：
2012-02-01
影响因子：
4
通讯作者：
John, Mina
中科院分区：
文献类型：
--
作者：
Keane, Niamh M.;Roberts, Steven G.;John, Mina
HIV-1突变减少或消除针对病毒感染细胞的CTL应答，在急性和慢性HIV感染中经常被选择。在群体HIV-1序列中，免疫选择是明显的，因为人类白细胞抗原（HLA）等位基因相关的CD 8 T细胞表位内或附近的氨基酸取代。在这些情况下，非适应表位对免疫识别敏感，直到逃逸突变使表位免疫原性降低。然而，一些基于人群的研究已经独立地鉴定了HLA相关的病毒变化，这导致了新的T细胞表位的形成，这表明这些变体或“新表位”引发的免疫应答为病毒而不是宿主提供了进化优势。在这里，我们研究了8个CD 8 T细胞反应的功能特征，导致病毒适应125个HLA基因分型的慢性HIV-1感染者。新表位包括由常见HLA等位基因限制的充分表征的免疫显性表位，并且在大多数情况下，与非适应表位的T细胞相比，针对新表位的T细胞应答显示出显著更大的功能亲合力和更高的IFN γ产生，但细胞毒性并不更强。然后在急性感染个体中在体内观察到与病毒载量上升一致的同源T细胞应答的新表位形成和出现。这些发现表明，HIV-1适应不仅消除了对早期靶向表位的免疫识别，而且还可能增加对其他表位的免疫识别，这些表位引起免疫显性但非保护性T细胞应答。这些数据与基于慢性HIV-1序列多样性的多价疫苗相关的免疫优势有关。Immunology and Cell Biology（2012）90，224-234; doi：10.1038/icb.2011.34; 2011年5月17日在线发表
HIV-1 mutations, which reduce or abolish CTL responses against virus-infected cells, are frequently selected in acute and chronic HIV infection. Among population HIV-1 sequences, immune selection is evident as human leukocyte antigen (HLA) allele-associated substitutions of amino acids within or near CD8 T-cell epitopes. In these cases, the non-adapted epitope is susceptible to immune recognition until an escape mutation renders the epitope less immunogenic. However, several population-based studies have independently identified HLA-associated viral changes, which lead to the formation of a new T-cell epitope, suggesting that the immune responses that these variants or 'neo-epitopes' elicit provide an evolutionary advantage to the virus rather than the host. Here, we examined the functional characteristics of eight CD8 T-cell responses that result from viral adaptation in 125 HLA-genotyped individuals with chronic HIV-1 infection. Neo-epitopes included well-characterized immunodominant epitopes restricted by common HLA alleles, and in most cases the T-cell responses against the neo-epitope showed significantly greater functional avidity and higher IFN gamma production than T cells for non-adapted epitopes, but were not more cytotoxic. Neo-epitope formation and emergence of cognate T-cell response coincident with a rise in viral load was then observed in vivo in an acutely infected individual. These findings show that HIV-1 adaptation not only abrogates the immune recognition of early targeted epitopes, but may also increase immune recognition to other epitopes, which elicit immunodominant but non-protective T-cell responses. These data have implications for immunodominance associated with polyvalent vaccines based on the diversity of chronic HIV-1 sequences. Immunology and Cell Biology (2012) 90, 224-234; doi:10.1038/icb.2011.34; published online 17 May 2011