HIV疫苗開(kāi)發(fā)面臨的挑戰(zhàn)之一就是缺乏一種準(zhǔn)確反映人對(duì)這種病毒產(chǎn)生的免疫應(yīng)答以及該病毒如何發(fā)生突變來(lái)逃避這種免疫應(yīng)答的動(dòng)物模型,。根據(jù)一項(xiàng)于2012年7月18日發(fā)表在Science Translational Medicine期刊上的新研究,，來(lái)自美國(guó)麻省總醫(yī)院拉根研究所、麻省理工學(xué)院和哈佛大學(xué)的研究人員報(bào)道,，他們利用移植人免疫系統(tǒng)的組分到免疫缺陷小鼠中而構(gòu)建出一種動(dòng)物模型,，從而解決了這些關(guān)鍵性問(wèn)題，而且這些動(dòng)物模型有潛力顯著性地減少測(cè)試候選疫苗所需的時(shí)間和成本,。研究通訊作者Todd Allen博士說(shuō),，“我們的研究表明不僅這些人化小鼠(humanized mice)對(duì)HIV產(chǎn)生免疫應(yīng)答，而且HIV能夠通過(guò)讓CD8殺傷性T細(xì)胞靶向的病毒蛋白發(fā)生突變而逃避這些免疫應(yīng)答,。我們第一次擁有一種能夠準(zhǔn)確復(fù)制至關(guān)重要的宿主-病原體相互作用的動(dòng)物模型，這一模型將有助于促進(jìn)人們開(kāi)發(fā)出有效的HIV疫苗,。”
在這項(xiàng)研究中,，研究人員測(cè)試了這種人化BLT小鼠,，即通過(guò)移植人骨髓干細(xì)胞和其他人組織到缺乏功能性免疫系統(tǒng)的小鼠體內(nèi)而構(gòu)建出的一種動(dòng)物模型。而且研究人員構(gòu)建一組人化BLT小鼠所用的細(xì)胞和組織是來(lái)自攜帶不同免疫系統(tǒng)HLA分子等位基因的人供者,，其中HLA分子標(biāo)記遭受病毒感染的細(xì)胞,，從而使得CD8 T細(xì)胞摧毀這些細(xì)胞。特定的HLA等位基因,，如HLA-B57,，在自然能夠控制HIV的人體內(nèi)更為常見(jiàn)。研究人員構(gòu)建出的這些小鼠當(dāng)中就有一些能夠表達(dá)這種重要的保護(hù)性等位基因,。
在這些小鼠被HIV感染六周之后,，研究人員發(fā)現(xiàn)HIV在已知能夠被CD8 T細(xì)胞靶向的區(qū)域快速地發(fā)生變化。他們的觀察結(jié)果表明不僅人化小鼠免疫系統(tǒng)對(duì)HIV產(chǎn)生免疫應(yīng)答,，而且HIV也不斷發(fā)生突變來(lái)躲避這些免疫應(yīng)答,，這與人體內(nèi)觀察到的情形類(lèi)似。在表達(dá)保護(hù)性HLA-B57等位基因的小鼠中,，正如能夠控制HIV病毒水平的病人一樣,，CD8 T細(xì)胞靶向HIV中一個(gè)至關(guān)重要的區(qū)域，從而阻止病毒發(fā)生突變和允許這些動(dòng)物更加有效地抑制HIV,。
Allen博士說(shuō),，他們當(dāng)前正在研究他們是夠通過(guò)接種疫苗在這些動(dòng)物體內(nèi)誘導(dǎo)出人HIV特異性的免疫應(yīng)答，以便能夠提供一種快速而又節(jié)約成本的動(dòng)物模型來(lái)測(cè)試不同疫苗控制或阻斷HIV感染的能力,，而且如果能夠做到這點(diǎn)的話,，那么他們將有一種非常強(qiáng)大的新工具來(lái)加速HIV疫苗開(kāi)發(fā)。(生物谷：Bioon.com)
本文編譯自Animal model replicates human immune response against HIV, could revolutionize HIV vaccine research
doi: 10.1126/scitranslmed.3003984
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Rapid Evolution of HIV-1 to Functional CD8+ T Cell Responses in Humanized BLT Mice
Timothy E. Dudek1, Daniel C. No1, Edward Seung2, Vladimir D. Vrbanac2, Lena Fadda1, Priyasma Bhoumik1, Christian L. Boutwell1, Karen A. Power1, Adrianne D. Gladden1, Laura Battis1, Elizabeth F. Mellors1, Trevor R. Tivey2, Xiaojiang Gao3, Marcus Altfeld1, Andrew D. Luster2, Andrew M. Tager2 and Todd M. Allen
The development of mouse/human chimeras through the engraftment of human immune cells and tissues into immunodeficient mice, including the recently described humanized BLT (bone marrow, liver, thymus) mouse model, holds great promise to facilitate the in vivo study of human immune responses. However, little data exist regarding the extent to which cellular immune responses in humanized mice accurately reflect those seen in humans. We infected humanized BLT mice with HIV-1 as a model pathogen and characterized HIV-1–specific immune responses and viral evolution during the acute phase of infection. HIV-1–specific CD8+ T cell responses in these mice were found to closely resemble those in humans in terms of their specificity, kinetics, and immunodominance. Viral sequence evolution also revealed rapid and highly reproducible escape from these responses, mirroring the adaptations to host immune pressures observed during natural HIV-1 infection. Moreover, mice expressing the protective HLA-B*57 allele exhibited enhanced control of viral replication and restricted the same CD8+ T cell responses to conserved regions of HIV-1 Gag that are critical to its control of HIV-1 in humans. These data reveal that the humanized BLT mouse model appears to accurately recapitulate human pathogen–specific cellular immunity and the fundamental immunological mechanisms required to control a model human pathogen, aspects critical to the use of a small-animal model for human pathogens.
