Department of Medicine, Johns Hopkins University School of Medicine, 733 N, Broadway, BRB 880, Baltimore, MD 21205, USA.
Retrovirology. 2013 Dec 12;10:152. doi: 10.1186/1742-4690-10-152.
Elite Controllers or Suppressors (ES) are HIV-1 positive individuals who maintain plasma viral loads below the limit of detection of standard clinical assays without antiretroviral therapy. Multiple lines of evidence suggest that the control of viral replication in these patients is due to a strong and specific cytotoxic T lymphocyte (CTL) response. The ability of CD8+ T cells to control HIV-1 replication is believed to be impaired by the development of escape mutations. Surprisingly, viruses amplified from the plasma of ES have been shown to contain multiple escape mutations, and it is not clear how immunologic control is maintained in the face of virologic escape.
We investigated the effect of escape mutations within HLAB-57-restricted Gag epitopes on the CD8+ T cell mediated suppression of HIV-1 replication. Using site directed mutagenesis, we constructed six NL4-3 based viruses with canonical escape mutations in one to three HLAB-57-restricted Gag epitopes. Interestingly, similar levels of CTL-mediated suppression of replication in autologous primary CD4+ T cells were observed for all of the escape mutants. Intracellular cytokine staining was performed in order to determine the mechanisms involved in the suppression of the escape variants. While low baseline CD8+ T cells responses to wild type and escape variant peptides were seen, stimulation of PBMC with either wild type or escape variant peptides resulted in increased IFN-γ and perforin expression.
These data presented demonstrate that CD8+ T cells from ES are capable of suppressing replication of virus harboring escape mutations in HLA-B*57-restricted Gag epitopes. Additionally, our data suggest that ES CD8+ T cells are capable of generating effective de novo responses to escape mutants.
精英控制者或抑制者（ES）是指在没有抗逆转录病毒治疗的情况下，血浆病毒载量保持在标准临床检测下限以下的 HIV-1 阳性个体。多条证据表明，这些患者对病毒复制的控制是由于强烈和特异性的细胞毒性 T 淋巴细胞（CTL）反应。人们认为，CD8+T 细胞控制 HIV-1 复制的能力因逃避突变的发展而受到损害。令人惊讶的是，从 ES 血浆中扩增的病毒已被证明含有多种逃避突变，目前尚不清楚在面对病毒逃避时如何维持免疫控制。
我们研究了 HLAB-57 限制的 Gag 表位内逃避突变对 CD8+T 细胞介导的 HIV-1 复制抑制的影响。使用定点诱变，我们构建了六种基于 NL4-3 的病毒，在一个到三个 HLAB-57 限制的 Gag 表位中都有典型的逃避突变。有趣的是，所有逃避突变体的 CTL 介导的复制抑制水平相似。为了确定逃避变异体抑制涉及的机制，进行了细胞内细胞因子染色。虽然在野生型和逃避变异型肽刺激时观察到低基线 CD8+T 细胞反应，但用野生型或逃避变异型肽刺激 PBMC 会导致 IFN-γ和穿孔素表达增加。
这些数据表明，来自 ES 的 CD8+T 细胞能够抑制携带 HLA-B*57 限制的 Gag 表位逃避突变的病毒复制。此外，我们的数据表明，ES CD8+T 细胞能够对逃避突变体产生有效的新反应。
