试图了解如何制造艾滋病疫苗的科学家们终于发现了该疫苗制造的最大障碍所在.事实证明,免疫系统确实可以产生能够后制造有效的HIV阻断抗体的细胞,但与此同时,免疫系统同样努力地确保这些细胞在它们有机会成熟之前将其清除.
    巴顿海恩斯(医学博士,位于杜克大学医学中心的艾滋病疫苗免疫研究中心主任,同时也是国家科学院院刊发表在网上的关于这个研究的早期版本的第一作者)说:“这些研究表明,一种潜在的具有保护功能的抗病毒中和性抗体是受免疫耐受控制的,这意味着一种新观点的出现,艾滋病病毒能有效地避开免疫系统B细胞武器的监测,同时也可能提供了研发疫苗的新标靶.”
    多年来,科学家们一致认为,位于抗感染第一道防线的B细胞根本无法“看到”艾滋病病毒.艾滋病病毒有隐藏其最敏感部分并躲避免疫系统监测的能力,而研究者通常认为这有助于解释为什么B细胞往往在受感染几个星期甚至几个月后才能被激活.
    但是,数年前,杜克大学的研究人员猜测,这些能广泛中和艾滋病病毒的抗体很可能无法在感染后的第一时间产生,由于这些抗体与引起自身免疫疾病的抗体如此相似,以至于免疫系统把它们当作潜在威胁,从而把他们清除.
    为清楚的了解这个病理过程,杜克大学的医学助理教授,同时也是这个研究的第一作者—洛朗韦尔科齐博士,和海恩斯一起进行了小鼠基因的改造,使得这只小鼠只能产生一种B细胞,它包含一种罕见但强大的能阻断艾滋病病毒的广谱中和性人类抗体.
    研究人员发现,小鼠的免疫系统能产生大量的表面携带人类中和性抗体的早期B细胞,但是,这些B细胞大部分都在它们有机会完全进化为具有分泌抗体功能的成熟B细胞之前就被清除了.
    韦尔科齐说:“这项工作意味着我们需要用不同的方式进行思考和研究:一个有效的疫苗到底是如何起作用的.好消息是,在大约85%的这类“正确的”B细胞被清除的同时,还有大约15%可以幸存下来并存在于血液循环里,但处于未激活状态.因此,疫苗设计的目标之一就是找到这些B细胞唤醒并让它们进行工作的方法.”
    海恩斯说:“我们现在已经发现为什么这类中和性抗体不能常规产生的一个主要原因:我们自身的免疫系统阻止了它们的产生,因为这类抗体被认为具有潜在危害,尽管事实并不是这样.这是一种令人意想不到的病毒在进化过程中获得的躲避免疫系统的方式.”
    海恩斯说,研究人员计划使用这个新的小鼠模型,以测试那些可以引导免疫系统产生强大的中和性HIV阻断抗体的方法.
关键词:艾滋病,艾滋病/艾滋病毒,获得性免疫缺陷综合症,生物技术,工程,艾滋病毒,艾滋病毒/艾滋病疫苗,人体免疫缺陷病毒,免疫接种,免疫学,疫苗,病毒学,杜克大学医学中心.

Biological catch-22 prevents induction of antibodiesthat block HIV
    Scientists seeking to understand how to make an AIDS vaccine have found the cause of a major roadblock. It turns out that the immune system can indeed produce cells with the potential to manufacture powerful HIV-blocking antibodies - but at the same time, the immune system works equally hard to make sure these cells are eliminated before they have a chance to mature.


    "These studies show that a potentially protective neutralizing antibody against a viral disease is under the control of immunological tolerance," said Barton Haynes, M.D., director of the Center for HIV/AIDS Vaccine Immunology (CHAVI) at Duke University Medical Center and senior author of the study appearing in the online early edition of the Proceedings of the National Academy of Sciences. "This represents a new insight into the way HIV effectively evades detection by the B cell arm of the immune system and may offer new directions for vaccine design."
    Over the years, scientists have assumed that B cells - one of the first lines of defense against infection - are simply not able to "see" the HIV virus. HIV has the ability to hide its most vulnerable parts from immune system surveillance, and researchers generally assumed that helped explain why B cells often took weeks and even months to arise following infection.
    But several years ago, Duke researchers hypothesized that the antibodies required to broadly neutralize HIV may not be produced in the first place because the immune system "sees" them as a potential threat - due to their similarity to antibodies that promote autoimmune disease - and destroys them.
    To see if this is indeed what happens, Laurent Verkoczy, Ph.D., assistant professor of medicine at Duke and the lead author of the study, and Haynes genetically engineered a mouse that could only produce B cells containing a rare but potent broadly neutralizing human antibody that is able to block HIV infection.
    Researchers found that the mouse\'s immune system produced plenty of early stage B cells bearing this human neutralizing antibody on their surface but eliminated most of them before they had a chance to fully evolve into more mature B cells capable of secreting the antibody.
    "This work may mean that we need to think and act very differently in envisioning how a successful vaccine may work," said Verkoczy. "The good news is that while about 85 percent of the "right" kind of B cells are eliminated, about 15 percent survive and wind up in circulating blood, but are turned off. One goal in vaccine design may be to figure out how to wake them up so they can go to work."
    "We have now unveiled a major reason why members of this class of neutralizing antibodies are not routinely made: Our own immune systems block their production because they are perceived as potentially harmful, when in reality, they are not," said Haynes. "This is a very unusual way the virus has developed to evade the immune system."
    Haynes says researchers plan on using the new mouse model to test ways to teach the immune system to  the production of powerful neutralizing antibodies capable of blocking HIV.

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