Yamamoto Takuya, Isogai Maya, Otake Kaori, Tsunetsugu-Yokota Yasuko
Department of Immunology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
Microbes Infect. 2006 Aug;8(9-10):2522-30. doi: 10.1016/j.micinf.2006.07.002. Epub 2006 Jul 31.
Numerous studies indicated that Nef is a pleiotropic factor. Although it has been shown that Nef impairs the antigen-presenting activity of dendritic cells, more recent studies have shown no such impairment. This issue is critical for designing a vaccine expressing Nef. To refine our knowledge regarding the effect of Nef on dendritic cells, we developed constitutive and inducible adenovirus vector systems that express high levels of Nef in monocyte-derived dendritic cells (MDDCs). We showed here that Nef expression clearly downregulated CD4 expression of MDDCs but had little or no effect on other surface molecules, including MHC class I. Nef also did not affect the functional maturation of MDDCs. Use of the inducible Nef-expression system clearly revealed that adenovirus infection per se modulates cytokine secretion and the expression of apoptosis-related molecules in MDDCs, whereas Nef had no effect on these functions. Moreover, the antigen-presenting activity of MDDCs was not disturbed by the presence of Nef. On the contrary, we found that Nef-expressing MDDCs generated from HIV-1-infected individuals efficiently activated Nef-reactive T cells. Therefore, although adenovirus vector may modulate some aspects of MDDC function, Nef-expressing adenovirus would be served as one of HIV vaccine candidates.
大量研究表明，Nef是一种多效性因子。尽管已有研究表明Nef会损害树突状细胞的抗原呈递活性，但最近的研究并未发现这种损害。这个问题对于设计表达Nef的疫苗至关重要。为了完善我们对Nef对树突状细胞影响的认识，我们开发了组成型和诱导型腺病毒载体系统，该系统可在单核细胞衍生的树突状细胞（MDDC）中高水平表达Nef。我们在此表明，Nef的表达明显下调了MDDC的CD4表达，但对包括MHC I类在内的其他表面分子几乎没有影响。Nef也不影响MDDC的功能成熟。使用诱导型Nef表达系统清楚地表明，腺病毒感染本身会调节MDDC中的细胞因子分泌和凋亡相关分子的表达，而Nef对这些功能没有影响。此外，Nef的存在并未干扰MDDC的抗原呈递活性。相反，我们发现从HIV-1感染个体产生的表达Nef的MDDC有效地激活了Nef反应性T细胞。因此，尽管腺病毒载体可能会调节MDDC功能的某些方面，但表达Nef的腺病毒将作为HIV疫苗候选之一。
