Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China.
Vaccine. 2011 Mar 21;29(14):2582-9. doi: 10.1016/j.vaccine.2011.01.049. Epub 2011 Feb 1.
Broad T-cell response is considered critical for HIV-1 vaccines to compensate viral diversity. Usually, a limited number of immunodominant epitopes are recognized in natural infections, as well as in vaccinations. Here, we seek to overcome immunofocusing of CD8 T Cell responses to HIV-1 CN54 gag DNA (delivered as a plasmid) in BalB/C mice by splitting it into fragments for reducing competition of recognition between dominant and sub-dominant epitopes. As expected, mice immunized with mixture of DNA fragments elicited significantly broader T cell responses than whole-length gag. We also further studied the effects when fragments and full-length DNA vaccines are combined for prime-boost vaccination. Interestingly, mice primed with full-length gag and boosted with DNA vaccine fragments induced similar T-cell response breadth as mice both primed and boosted by fragments DNA. In contrast, mice primed with DNA vaccine fragments and boosted with full-length gag failed to broaden T cell responses, once again, only the dominant epitopes were recognized. In summary, our study demonstrated that "fragmentation strategy" can indeed broaden T cell responses. This enhancement is more likely achieved in boosting stage. This study offers a promising way to design a vaccine with higher chance covering the highly diversified circulating strains.
广泛的 T 细胞反应被认为对于 HIV-1 疫苗至关重要，以弥补病毒的多样性。通常，在自然感染和接种疫苗中，只有有限数量的免疫优势表位被识别。在这里，我们试图通过将 HIV-1 CN54 gag DNA（作为质粒递送）分成片段来克服 CD8 T 细胞对其的免疫聚焦，从而减少优势和次优势表位之间的识别竞争。正如预期的那样，用 DNA 片段混合物免疫的小鼠比全长 gag 引发了更广泛的 T 细胞反应。我们还进一步研究了当片段和全长 DNA 疫苗联合进行初次-加强免疫接种时的效果。有趣的是，用全长 gag 进行初次免疫并用 DNA 疫苗片段加强免疫的小鼠诱导的 T 细胞反应广度与用全长 DNA 疫苗片段进行初次和加强免疫的小鼠相似。相比之下，用 DNA 疫苗片段进行初次免疫并用全长 gag 进行加强免疫的小鼠未能扩大 T 细胞反应，再次仅识别优势表位。总之，我们的研究表明，“碎片化策略”确实可以扩大 T 细胞反应。这种增强更有可能在加强阶段实现。这项研究为设计一种更有可能覆盖高度多样化的循环株的疫苗提供了一种有前途的方法。
