Selection, transmission, and reversion of an antigen-processing cytotoxic T-lymphocyte escape mutation in human immunodeficiency virus type 1 infection
Selection, transmission, and reversion of an antigen-processing cytotoxic T-lymphocyte escape mutation in human immunodeficiency virus type 1 infection
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DOI：
10.1128/jvi.78.13.7069-7078.2004
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发表时间：
2004-07-01
影响因子：
5.4
通讯作者：
Walker, BD
中科院分区：
文献类型：
--
作者：
Allen, TM;Altfeld, M;Walker, BD
许多研究现在支持人类免疫缺陷病毒1型（HIV-1）的进化受到免疫选择压力的影响，人群研究显示特定的HLA等位基因和定义的细胞毒性T淋巴细胞表位内的突变之间存在关联。在这里，我们结合联合收割机序列数据和功能研究的CD 8 T细胞反应，以证明等位基因特异性免疫压力也选择突变侧翼的CD 8表位，损害抗原处理。在表达HLA-A3的人中，我们证明了对正常免疫显性Gag KK 9表位的C-末端侧翼残基中的突变的一致选择，该突变阻止其加工和呈递，导致CD 8 T细胞应答的快速下降。该单个氨基酸取代也位于第二HLA-A3限制性表位内，该突变直接损害CD 8 T细胞的识别。将突变传递给表达HLA-A3的受试者，可防止诱导对两种表位的正常免疫显性急性期应答。然而，随后在体内逆转的突变是一致的延迟诱导新的CD 8 T细胞的反应，这两个表位。这些数据表明，HIV-1表位侧翼区域内的突变可以削弱已建立的CD 8 T细胞应答的识别，并且这些突变的传递改变了急性期CD 8（+）T细胞应答。此外，在没有原始免疫压力的情况下，这些突变的逆转揭示了免疫选择进化变化的潜在可塑性。
Numerous studies now support that human immunodeficiency virus type 1 (HIV-1) evolution is influenced by immune selection pressure, with population studies showing an association between specific HLA alleles and mutations within defined cytotoxic T-lymphocyte epitopes. Here we combine sequence data and functional studies of CD8 T-cell responses to demonstrate that allele-specific immune pressures also select for mutations flanking CD8 epitopes that impair antigen processing. In persons expressing HLA-A3, we demonstrate consistent selection for a mutation in a C-terminal flanking residue of the normally immunodominant Gag KK9 epitope that prevents its processing and presentation, resulting in a rapid decline in the CD8 T-cell response. This single amino acid substitution also lies within a second HLA-A3-restricted epitope, with the mutation directly impairing recognition by CD8 T cells. Transmission of the mutation to subjects expressing HLA-A3 was shown to prevent the induction of normally immunodominant acute-phase responses to both epitopes. However, subsequent in vivo reversion of the mutation was coincident with delayed induction of new CD8 T-cell responses to both epitopes. These data demonstrate that mutations within the flanking region of an HIV-1 epitope can impair recognition by an established CD8 T-cell response and that transmission of these mutations alters the acute-phase CD8(+) T-cell response. Moreover, reversion of these mutations in the absence of the original immune pressure reveals the potential plasticity of immunologically selected evolutionary changes.