Antibody-Mediated Protection against Mucosal Simian-Human Immunodeficiency Virus Challenge of Macaques Immunized with Alphavirus Replicon Particles and Boosted with Trimeric Envelope Glycoprotein in MF59 Adjuvant
Antibody-Mediated Protection against Mucosal Simian-Human Immunodeficiency Virus Challenge of Macaques Immunized with Alphavirus Replicon Particles and Boosted with Trimeric Envelope Glycoprotein in MF59 Adjuvant
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DOI：
10.1128/jvi.02533-09
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发表时间：
2010-06-01
影响因子：
5.4
通讯作者：
Srivastava, Indresh K.
中科院分区：
文献类型：
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作者：
Barnett, Susan W.;Burke, Brian;Srivastava, Indresh K.
我们先前已经证明，恒河猴可以部分抵抗高剂量静脉注射猴-人类免疫缺陷病毒SHIVSF162P4的攻击，随后用嵌合的重组VEE/SINα病毒(源自委内瑞拉马脑炎病毒[VEE]和Sindbis病毒[SIN])的α病毒复制子颗粒(VRP)和MF59佐剂(R.Xu，I.K.Sriastava，C.E.Greer，I.Zarkikh，Z.K.Kraft，L.Kuller，J.Polo，S.W.Barnett和L.Stamatos，L.Stamatos)中的三聚体Env蛋白(R.Xu，I.K.Sriastava，C.E.Greer，I.Zarkikh，Z.Kraft，L.Kuller，J.Polo，S.W.Barnett和L.Stamatos，L.Stamatos，艾滋病研究人员。嗯。逆转录病毒22：1022-1030,2006)。这种保护不需要针对猴免疫缺陷病毒(SIV)Gag的T细胞免疫反应。我们将这些发现延伸到这里，以证明抗体介导的猕猴抵抗粘膜攻击的保护作用，使用PRIME-Boost方案结合肌肉内和粘膜传递途径。免疫组猕猴先用VRP免疫，然后用MF59佐剂中的Env蛋白加强免疫，或单独肌肉注射VRP，然后用SHIVSF162P4攻击(直肠内攻击)。结果表明，这些疫苗都能不同程度地保护猕猴免受黏膜SIV攻击，但最值得注意的是，所有接受肌肉注射VRP Prime和Env蛋白Boost的猕猴都得到了完全保护。观察到病毒中和抗体和结合抗体的滴度以及在攻击前和预防感染前测量的抗Env抗体的亲和力之间存在统计学上的显着关联。这些结果突出了甲病毒复制子载体PRIME加Env蛋白Boost疫苗方法在诱导保护性抗体反应方面的优点，并且对于促进我们对相关粘膜入口处针对HIV感染的潜在免疫保护的理解具有特别重要的意义。
We have previously shown that rhesus macaques were partially protected against high-dose intravenous challenge with simian-human immunodeficiency virus SHIVSF162P4 following sequential immunization with alphavirus replicon particles (VRP) of a chimeric recombinant VEE/SIN alphavirus (derived from Venezuelan equine encephalitis virus [VEE] and the Sindbis virus [SIN]) encoding human immunodeficiency virus type 1 HIV-1(SF162)gp140 Delta V2 envelope (Env) and trimeric Env protein in MF59 adjuvant (R. Xu, I. K. Srivastava, C. E. Greer, I. Zarkikh, Z. Kraft, L. Kuller, J. M. Polo, S. W. Barnett, and L. Stamatatos, AIDS Res. Hum. Retroviruses 22:1022-1030, 2006). The protection did not require T-cell immune responses directed toward simian immunodeficiency virus (SIV) Gag. We extend those findings here to demonstrate antibody-mediated protection against mucosal challenge in macaques using prime-boost regimens incorporating both intramuscular and mucosal routes of delivery. The macaques in the vaccination groups were primed with VRP and then boosted with Env protein in MF59 adjuvant, or they were given VRP intramuscular immunizations alone and then challenged with SHIVSF162P4 (intrarectal challenge). The results demonstrated that these vaccines were able to effectively protect the macaques to different degrees against subsequent mucosal SHIV challenge, but most noteworthy, all macaques that received the intramuscular VRP prime plus Env protein boost were completely protected. A statistically significant association was observed between the titer of virus neutralizing and binding antibodies as well as the avidity of anti-Env antibodies measured prechallenge and protection from infection. These results highlight the merit of the alphavirus replicon vector prime plus Env protein boost vaccine approach for the induction of protective antibody responses and are of particular relevance to advancing our understanding of the potential correlates of immune protection against HIV infection at a relevant mucosal portal of entry.