Immunization of human volunteers with hepatitis C virus envelope glycoproteins elicits antibodies that cross-neutralize heterologous virus strains.
Immunization of human volunteers with hepatitis C virus envelope glycoproteins elicits antibodies that cross-neutralize heterologous virus strains.
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用丙型肝炎病毒包膜糖蛋白对人类志愿者进行免疫，会引发交叉中和异源病毒株的抗体。
DOI：
10.1093/infdis/jir399
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发表时间：
2011
期刊：
影响因子：
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通讯作者：
McKeating,JaneA
中科院分区：
文献类型：
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作者：
Stamataki,Zania;Coates,Stephen;Abrignani,Sergio;Houghton,Michael;McKeating,JaneA
响应于疫苗接种而产生交叉反应性中和抗体（nAb）一直是RNA病毒如人类免疫缺陷病毒的主要障碍（在[3]中综述）。我们报道了用HCV E1 E2异二聚体或来自基因型1a HCV-1株的截短的可溶性E2免疫啮齿类动物可引发高滴度交叉反应性nAb [2]。在这里，我们报告，免疫健康的人类志愿者与相同的重组HCV-1 E1 E2糖蛋白可以诱导交叉反应性中和抗体反应。评估来自8名健康免疫志愿者的血清样品中和一组HCVpp菌株的能力。简言之，将最终稀释度为1/100的免疫前和免疫后血清样品与编码荧光素酶报告基因的HCVpp在37 ℃下预孵育1小时，然后在37 ℃下感染Huh-7.5细胞6小时. 72小时后通过监测荧光素酶活性定量感染（图1）。所有免疫血清样品中和表达密切相关的基因型1a H77糖蛋白、异源基因型1b糖蛋白CON 1和OH 8以及更远相关的基因型2a菌株J6的HCVpp，尽管效率降低。免疫前和免疫后血清样品对小鼠白血病病毒假颗粒感染没有影响（图1）。为了确定免疫血清样品中和HCVDNA的能力，我们测试了表达H77和J6结构蛋白的嵌合JFH-1病毒对免疫血清样品抑制的敏感性。所有血清样品都明显能够中和两种异源HCV病毒，尽管在2a病毒的情况下效率较低（图1）。我们的实验证明，用来自基因型1a菌株的重组E1 E2糖蛋白免疫人类志愿者可产生抗体，该抗体可交叉中和来自基因型1a、1b和2a的异源菌株的体外感染性。尽管有迹象表明，在靶向病毒编码的糖蛋白的抗体存在的情况下，HCV可以通过相邻接触细胞之间的直接转移在体外传播[4]，但最近对嵌合SCID-uPA小鼠的研究已经产生了令人鼓舞的结果，即nAb在预防或改善体内病毒感染方面的保护作用[5，6]。我们使用HCVpp和匹配HCV 3菌株的研究扩展了Ray等人的工作[1]，并证明人类志愿者的疫苗接种产生了针对异源1a、1b和2a HCV基因型的具有显著交叉中和活性的抗体应答，阻止了HCV基因型的持续临床开发。
Generation of cross-reactive neutralizing antibodies (nAb) in response to vaccination has been a major hurdle for RNA viruses such as human immunodeficiency virus (reviewed in [3]). We reported that immunizing rodents with HCV E1E2 heterodimer or truncated soluble E2 derived from the genotype 1a HCV-1 strain elicited high titer crossreactive nAb [2]. Here we report that immunization of healthy human volunteers with the same recombinant HCV-1 E1E2 glycoproteins can induce a cross-reactive neutralizing antibody response. Serum samples from 8 healthy immunized volunteers were assessed for their ability to neutralize a panel of HCVpp strains. Briefly, pre-and postimmune serum samples at a final dilution of 1/100 were preincubated with HCVpp encoding a luciferase reporter for 1 hour at 37 C prior to infecting Huh-7.5 cells for 6 hours at 37 C. Infection was quantified after 72 hours by monitoring luciferase activity (Figure 1). All immune serum samples neutralized HCVpp expressing the closely related genotype 1a H77 glycoproteins, the heterologous genotype 1b glycoproteins CON1 and OH8, and the more distantly related genotype 2a strain J6, albeit with reduced efficiency. Preimmune and postimmune serum samples had no effect on murine leukemia virus pseudoparticle infection (Figure 1). To ascertain the ability of immune serum samples to neutralize HCVcc, we tested the sensitivity of chimeric JFH-1 viruses expressing H77 and J6 structural proteins to inhibition by immune serum samples. All serum samples were clearly capable of neutralizing both heterologous HCVcc viruses, although less efficiently in the case of the 2a virus (Figure 1). Our experiments demonstrate that immunization of human volunteers with recombinant E1E2 glycoproteins derived from the genotype 1a strain elicits antibodies that can cross-neutralize the in vitro infectivity of heterologous strains derived from genotypes 1a, 1b, and 2a. Despite indications that HCV can transmit in vitro in the presence of antibodies targeting the viral encoded glycoproteins via direct transfer between adjacent contacting cells [4], recent studies with chimeric SCID-uPA mice have yielded encouraging results for a protective role of nAb to prevent or ameliorate virus infection in vivo [5, 6]. Our studies using HCVpp and matching HCVcc strains expand upon the work of Ray et al [1] and demonstrate that vaccination of human volunteers elicits antibody responses with significant crossneutralizing activity against heterologous 1a, 1b, and 2a HCV genotypes, warranting the continued clinical development of