HLA-B57/B*5801 Human Immunodeficiency Virus Type 1 Elite Controllers Select for Rare Gag Variants Associated with Reduced Viral Replication Capacity and Strong Cytotoxic T-Lymphotye Recognition
HLA-B57/B*5801 Human Immunodeficiency Virus Type 1 Elite Controllers Select for Rare Gag Variants Associated with Reduced Viral Replication Capacity and Strong Cytotoxic T-Lymphotye Recognition
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DOI：
10.1128/jvi.02265-08
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发表时间：
2009-03-15
影响因子：
5.4
通讯作者：
Walker, Bruce D.
中科院分区：
文献类型：
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作者：
Miura, Toshiyuki;Brockman, Mark A.;Walker, Bruce D.
人类免疫缺陷病毒1型（HIV-1）精英控制者（EC）在没有抗病毒治疗的情况下维持低于商业检测限（< 50 RNA拷贝/ml）的病毒血症，但控制机制仍不清楚。HLA-B57和密切相关的等位基因B*5801与增强的控制特别相关，并识别相同的Gag（240-249）TW 10表位。该表位内的典型逃逸突变（T242 N）降低了慢性感染者的病毒复制能力;然而，对B57/B*5801 EC中残留复制病毒的TW 10表位序列以及该表位内的突变可能影响稳态病毒血症的程度知之甚少。在此，我们分析了总共50例B57/B*5801阳性受试者（23例EC和27例病毒血症受试者）中的TW 10。来自EC和病毒血症受试者的自体血浆病毒序列经常携带典型的细胞毒性T淋巴细胞（CTL）选择性突变T242 N（分别为15/23个序列[65.2%]和23/27个序列[85.1%]; P = 0.18）。然而，在HIV控制者中发现了其他独特的突变体，包括TW 10内部和侧翼，这些突变体与体外病毒复制能力的更大降低相关。此外，通过γ干扰素特异性酶联免疫斑点试验检测到对许多这些独特的TW 10变体的强烈CTL应答。这些数据表明持久控制HIV复制的双重机制，由CTL逃逸突变引起的病毒适应性丧失以及对所产生的变体表位的强CD 8 T细胞免疫应答组成。
Human immunodeficiency virus type 1 (HIV-1) elite controllers (EC) maintain viremia below the limit of commercial assay detection (< 50 RNA copies/ml) in the absence of antiviral therapy, but the mechanisms of control remain unclear. HLA-B57 and the closely related allele B*5801 are particularly associated with enhanced control and recognize the same Gag(240-249) TW10 epitope. The typical escape mutation (T242N) within this epitope diminishes viral replication capacity in chronically infected persons; however, little is known about TW10 epitope sequences in residual replicating viruses in B57/B*5801 EC and the extent to which mutations within this epitope may influence steady-state viremia. Here we analyzed TW10 in a total of 50 B57/B*5801-positive subjects (23 EC and 27 viremic subjects). Autologous plasma viral sequences from both EC and viremic subjects frequently harbored the typical cytotoxic T-lymphocyte (CTL)-selected mutation T242N (15/23 sequences [65.2%] versus 23/27 sequences [85.1%], respectively; P = 0.18). However, other unique mutants were identified in HIV controllers, both within and flanking TW10, that were associated with an even greater reduction in viral replication capacity in vitro. In addition, strong CTL responses to many of these unique TW10 variants were detected by gamma interferon-specific enzyme-linked immunospot assay. These data suggest a dual mechanism for durable control of HIV replication, consisting of viral fitness loss resulting from CTL escape mutations together with strong CD8 T-cell immune responses to the arising variant epitopes.