Medizinische Poliklinik, LMU, 80336, Munich, Germany.
Med Microbiol Immunol. 2012 May;201(2):201-11. doi: 10.1007/s00430-011-0222-1. Epub 2011 Dec 27.
Antiretroviral treatment directed against HIV is highly effective, yet limited by drug resistance mutations. We hypothesized that CD8 T cells targeting drug-resistant HIV mutants are able to inhibit viral replication in the setting of a failing therapeutic regimen. We evaluated CD8 T-cell responses and mapped epitopes in HIV-infected patients by interferon-gamma Elispot and intracellular cytokine staining. Autologous virus was sequenced by RT-PCR. Viral replication inhibition assays were performed using M184V mutant virus and CD8 T cell lines. CD8 T-cell responses toward the regions of viral drug resistance mutations in Pol are frequent. Focusing on the M184V mutation, A02:01-YQYVDDLYV and A02:01-VIYQYVDDLYV were identified as optimal epitopes for the majority of study subjects. Viral replication of M184V HIV mutants was inhibited by CD8 T cell lines in vitro. In case of a failing lamivudine/emtricitabine containing regimen, individuals with a CD8 T-cell response toward M184V had a significant lower viral load than those without a CD8 response (p = 0.005). Two study subjects even achieved an undetectable viral load. Our data suggest that control of M184V mutant virus by CD8 T-cell responses is possible in vitro and in vivo. This control has important implications for therapeutic vaccination strategies.
抗逆转录病毒治疗针对 HIV 非常有效，但受到耐药突变的限制。我们假设针对耐药 HIV 突变体的 CD8 T 细胞能够抑制治疗方案失败时的病毒复制。我们通过干扰素-γ Elispot 和细胞内细胞因子染色评估了 HIV 感染患者的 CD8 T 细胞反应，并对其进行了定位。通过 RT-PCR 对自身病毒进行了测序。使用 M184V 突变病毒和 CD8 T 细胞系进行了病毒复制抑制测定。在 Pol 中的病毒耐药突变区域中，CD8 T 细胞反应频繁发生。针对 M184V 突变，A02:01-YQYVDDLYV 和 A02:01-VIYQYVDDLYV 被确定为大多数研究对象的最佳表位。CD8 T 细胞系在体外抑制了 M184V HIV 突变体的复制。在拉米夫定/恩曲他滨含药方案失败的情况下，对 M184V 有 CD8 细胞反应的个体的病毒载量明显低于没有 CD8 反应的个体（p = 0.005）。有两名研究对象甚至达到了不可检测的病毒载量。我们的数据表明，CD8 T 细胞反应可在体外和体内控制 M184V 突变病毒。这种控制对治疗性疫苗策略具有重要意义。
