PNAS：动摇艾滋病疫苗的根基

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近几十年，艾滋病疫苗可以说是整个科学界共同追寻的圣杯。到目前为止，该领域的投资已达数百万美元，无数科学家为此不懈努力却仍未获得成功。人们普遍认为，保护性疫苗只要能够诱导出适量的中和性抗体就可以预防病毒感染，这也是艾滋病疫苗研发的理论基础。然而，Emory大学的一项最新研究对此提出了挑战。


研究人员给猴子接种了艾滋病疫苗，使其血液中产生强力的中和性抗体，但有些猴艾滋病毒依然可以建立感染。研究显示，这些艾滋病毒似乎对中和性抗体不屑一顾，甚至都不用通过突变来躲避。这项研究发表在八月十日的美国国家科学院院刊PNAS杂志上。


此前有不少研究表明，试验性的艾滋病疫苗可以帮助大多数猴子抵御反复的感染。而这项研究的发现犹如当头一盆冷水，让人清醒地认识到问题的复杂性，文章资深作者Cynthia Derdeyn教授说。


为了逃避免疫系统的压力，人体内的HIV一直在不断的突变。“我们本来以为突破免疫防线的病毒应该是抵抗中和性抗体的，”她说。“发现艾滋病毒直接无视抗体，令我们感到非常惊讶。”


研究人员一直在用恒河猴测试艾滋病疫苗。他们给这种猴子接种疫苗，然后反复让其接触SIV，在第12次接触SIV后，未接种疫苗的猴子全部感染了艾滋病，而最有效的疫苗可以保护70%的猴子不受感染。


“艾滋病疫苗的确有保护作用，但并不能完全预防，”Derdeyn说。“因此我们对突破防御的病毒进行了研究。”


研究人员选取了一些在接种疫苗后仍被感染的猴子，并分离出建立感染的SIV病毒株。研究显示，这些猴子体内的抗体在体外是能够中和上述病毒的，但它们在体内却失效了。这说明体外测试不足以反映体内的真实情况，可能中和性抗体在血液中很多，但在发生感染的粘膜表面却比较少。

来源：生物通

Anny

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Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses.

Burton SL1, Kilgore KM1, Smith SA1, Reddy S1, Hunter E2, Robinson HL3, Silvestri G2, Amara RR4, Derdeyn CA5.

Abstract
Although the correlates of immunological protection from human immunodeficiency virus or simian immunodeficiency virus infection remain incompletely understood, it is generally believed that medium to high titers of serum neutralizing antibodies (nAbs) against the challenge virus will prevent infection. This paradigm is based on a series of studies in which passive transfer of HIV-specific nAbs protected rhesus macaques (RMs) from subsequent mucosal challenge with a chimeric human/simian immunodeficiency virus. However, it is unknown whether nAb titers define protection in the setting of active immunization. Here we determined serum nAb titers against breakthrough transmitted/founder (T/F) SIVsmE660-derived envelope glycoprotein (Env) variants from 14 RMs immunized with SIVmac239-based DNA-prime/modified vaccinia virus Ankara-boost vaccine regimens that included GM-CSF or CD40L adjuvants and conferred significant but incomplete protection against repeated low-dose intrarectal challenge. A single Env variant established infection in all RMs except one, with no identifiable genetic signature associated with vaccination breakthrough compared with T/F Envs from four unvaccinated monkeys. Breakthrough T/F Env pseudoviruses were potently neutralized in vitro by heterologous pooled serum from chronically SIVsmE660-infected monkeys at IC50 titers exceeding 1:1,000,000. Remarkably, the T/F Env pseudoviruses from 13 of 14 monkeys were also susceptible to neutralization by autologous prechallenge serum at in vitro IC50 titers ranging from 1:742-1:10,832. These titers were similar to those observed in vaccinated RMs that remained uninfected. These data suggest that the relationship between serum nAb titers and protection from mucosal SIV challenge in the setting of active immunization is more complex than previously recognized, warranting further studies into the balance between immune activation, target cell availability, and protective antibody responses.

http://www.pnas.org/content/early/2015/08/05/1509731112.long