Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
Retrovirology. 2014 Feb 4;11:13. doi: 10.1186/1742-4690-11-13.
A small minority of HIV-1-infected individuals show low levels of immune activation and do not develop immunodeficiency despite high viral loads. Since the accessory viral Nef protein modulates T cell activation and plays a key role in the pathogenesis of AIDS, we investigated whether specific properties of Nef may be associated with this highly unusual clinical outcome of HIV-1 infection.
Comprehensive functional analyses of sequential HIV-1 strains from three viremic long-term non-progressors (VNP) showed that they encode full-length Nef proteins that are capable of modulating CD4, CD28, CD8ß, MHC-I and CD74 cell surface expression. Similar to Nef proteins from HIV-1-infected individuals with progressive infection (P-Nefs) and unlike Nefs from simian immunodeficiency viruses (SIVs) that do not cause chronic immune activation and disease in their natural simian hosts, VNP-Nefs were generally unable to down-modulate TCR-CD3 cell surface expression to block T cell activation and apoptosis. On average, VNP-Nefs suppressed NF-AT activation less effectively than P-Nefs and were slightly less active in enhancing NF-κB activity. Finally, we found that VNP-Nefs increased virion infectivity and enhanced HIV-1 replication and cytopathicity in primary human cells and in ex vivo infected lymphoid tissues.
Our results show that nef alleles from VNPs and progressors of HIV-1 infection show only modest differences in established functions. Thus, the lack of chronic immune activation and disease progression in HIV-1-infected VNPs is apparently not associated with unusual functional properties of the accessory viral Nef protein.
尽管 HIV-1 感染者的病毒载量很高，但一小部分感染者的免疫激活水平较低，且不会发展为免疫缺陷。由于辅助病毒 Nef 蛋白可调节 T 细胞激活，并在艾滋病的发病机制中发挥关键作用，因此我们研究了 Nef 的特定特性是否与 HIV-1 感染的这种非常不寻常的临床结果相关。
对来自三名病毒血症长期非进展者（VNP）的连续 HIV-1 株进行的全面功能分析表明，它们编码全长 Nef 蛋白，能够调节 CD4、CD28、CD8β、MHC-I 和 CD74 细胞表面表达。与进展性感染的 HIV-1 感染者（P-Nefs）的 Nef 蛋白相似，与不会在其自然灵长类宿主中引起慢性免疫激活和疾病的猴免疫缺陷病毒（SIVs）的 Nef 蛋白不同，VNP-Nef 通常无法下调 TCR-CD3 细胞表面表达以阻断 T 细胞激活和凋亡。平均而言，VNP-Nef 抑制 NF-AT 激活的效果不如 P-Nef，增强 NF-κB 活性的能力略差。最后，我们发现 VNP-Nef 增加了病毒粒子的感染力，并增强了 HIV-1 在原代人细胞和体外感染的淋巴组织中的复制和细胞病变作用。
我们的结果表明，来自 VNP 和 HIV-1 感染者进展者的 nef 等位基因在已建立的功能方面仅显示出适度差异。因此，HIV-1 感染者中慢性免疫激活和疾病进展的缺乏显然与辅助病毒 Nef 蛋白的不寻常功能特性无关。
