TSRI and IAVI researchers harness antibody evolution on the path to an AIDS vaccine

出版时间:星期日,September 11,2016—05:06 inHealth & Medicine

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这项新的研究表明,免疫系统可以被提示模仿并加速一个罕见的自然过程,在这个过程中,抗体慢慢进化,以更好地针对不断变异的艾滋病毒。这里显示的是分子eod-gt8 60mer,用于团队的
Image courtesy of The Scripps Research Institute.

由斯克里普斯研究所(TSRI)和国际艾滋病疫苗倡议(IAVI)徳赢手机版的科学家领导的一系列新研究描述了一种潜在的疫苗接种策略,以启动广泛有效的抗体的选择和进化,以防止艾滋病毒感染。研究人员计划在即将进行的人体临床试验中测试这一策略。The new studies,9月8日出版,2016,in the journals细胞科学类,showed the immune system can be prompted to mimic and accelerate a rare natural process during which antibodies slowly evolve to become better and better at targeting the constantly mutating HIV virus.

"Although we still have a long way to go,we're making really good progress toward a human vaccine," said William Schief,professor at TSRI and director of vaccine design for IAVI's Neutralizing Antibody Center (NAC) at TSRI,他们的实验室开发了许多在这些研究中测试的疫苗蛋白。

Schief co-led several of the new studies with TSRI Professor David Nemazee;Dennis BurtonJames&Jessie,IAVI NAC和美国国立卫生研究院(NIH)艾滋病毒/艾滋病疫苗免疫学和免疫原发现中心(Chavi-ID)的TSRI免疫学和微生物科学系副主任兼科学主任;Ian WilsonHansen Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI.

Developing a Blueprint

A vaccine needs to elicit those rare antibodies,called "broadly neutralizing antibodies" (bnAbs),它能与各种各样的HIV病毒株抗争,而且需要很快地诱导它们。

One strategy to accomplish this,which 徳赢手机版scientists at TSRI have dubbed the "reductionist" strategy,is to find which antibody mutations are most important for making them effective against HIV,then to "prime" the immune system to start making antibody precursors.从那里,徳赢手机版scientists hope to prompt one important mutation after another with a series of different "booster" shots,deliberately building up a bnAb one step at a time.

在杂志上最近的一项研究中PLOS病原菌,科学家们徳赢手机版制作了一张3d的结构图,图上的艾滋病毒被称为CD4结合位点。如果抗体成功攻击这个部位,徳赢手机版科学家认为,most strains of HIV could be crippled.The researchers also created high-resolution maps of bnAbs that could bind to the CD4 binding site.

"This is one of the most complete blueprints we've had for this target," said Jean-Philippe Julien,研究时威尔逊实验室的研究助理,曾与TSRI研究助理Joseph Jardine共同担任该研究的第一作者,IAVI研究科学家Devin徳赢手机版 Sok和Bryan Briney,assistant professor of immunology at TSRI.

The 徳赢手机版scientists then studied stripped-down versions of the bnAbs to see exactly which components were important in targeting the CD4 binding site.

With the results from thePLOS病原菌study,研究人员最终得出了突变最重要的指南。他们也对哪种抗体诱导分子有了更好的认识,称为免疫原,可以在适当的时间用增强剂注射来触发正确的突变。

"We're figuring how to boost antibodies to the next step--how to keep walking them along the path to increased breadth and potency after we get them started with a priming shot," said Jardine.

Training Promising Antibodies

这一发现为三项新研究奠定了基础。对于第一个,发表于细胞,researchers tested a priming immunogen,接着是来自Schief实验室的一系列增强免疫原。在小鼠模型中测试免疫原,developed by the Nemazee lab,which was engineered to have the genes (the raw materials) to make antibodies with the right mutations to target the CD4 binding site.

The team found that the elicited antibodies more closely resembled mature antibodies.免疫原的序列完成了它们的工作。

“研究表明免疫原起作用,”线虫说。“它们使产生抗体的B细胞向正确的方向变异。”

“诱导抗体与成熟的bnabs有许多共同的遗传特征,能够中和一个本地的HIV分离株以及多个其他的HIV分离株,我们对它们进行了轻微的修改,使它们更容易中和,”Briney补充道,他是索克研究的第一作者,JardineIAVI和TSRI工作人员科学家丹尼尔·徳赢手机版库普和TSRI研究助理帕特里克·斯科格。"We will probably need additional booster immunogens to elicit antibodies that can broadly neutralize native HIV isolates,但我们的结果表明我们走的是正确的道路。”

In the second细胞study,led by John R.Mascola at the NIH's National Institute of Allergy and Infectious Disease (NIAID) Vaccine Research Center and Frederick W.Alt,波士顿儿童医院和哈佛医学院的霍华德休斯医学研究所(HHMI)研究员,along with TSRI co-authors,还原论的方法更进一步,showing that it could induce antibodies in mouse models with immune systems that can create an even wider range of antibodies--more similar to the human immune system.

结果来自科学类研究进一步支持了还原剂疫苗的方法。For the study,the researchers took on an even bigger challenge--to "prime" antibodies in a mouse model with a human-like immune system developed by Kymab Ltd,a UK-based company.

Kymab小鼠模型更复杂的免疫系统使得疫苗蛋白更难找到并激活“前体”细胞,这些前体细胞有可能产生抗CD4结合位点的bnabs。事实上,研究人员估计,在大约7500万个抗体产生细胞中,每只Kymab小鼠平均只含有一个这样的前体细胞(有些小鼠不含前体细胞)。

尽管有“大海捞针”的挑战,徳赢手机版科学家发现,他们的疫苗启动蛋白在三分之一到一半的受试小鼠体内激活了适当的抗体前体。suggesting this feat would also be possible in humans,where the targeted precursor cells are more plentiful.“这似乎是一个更高的标准,比我们将面对的人类,”希夫说。

“我们正在进行的还原剂疫苗方法有望不仅导致艾滋病毒疫苗,但也有可能应用于其他具有挑战性的疫苗目标。who served as co-first author of the科学类与Briney研究,Jardine和Kulp。

研究人员还赞扬了他们强大的国际合作。"Our phenomenal results with the team at The Scripps Research Institute came from work at the interfaces--and boundaries--of vaccine technology,免疫学,蛋白质工程和结构生物学,”艾伦·布拉德利教授说,Kymab的首席技术官和Wellcome Trust Sanger Institute的名誉董事。

IAVI and partners are planning for a clinical trial for next year to further develop and test whether the reductionist vaccine strategy--starting with activating the right precursors--will work in humans.If successful,the next step will be to test their booster immunogens.

来源:Scripps Research Institute

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