Recombinant human immunodeficiency Pr55(gag) virus-like particles presenting chimeric envelope glycoproteins induce cytotoxic T-cells and neutralizing antibodies
Recombinant human immunodeficiency Pr55(gag) virus-like particles presenting chimeric envelope glycoproteins induce cytotoxic T-cells and neutralizing antibodies
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DOI：
10.1006/viro.1997.8668
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发表时间：
1997-08-18
期刊：
影响因子：
3.7
通讯作者：
Wagner, R
中科院分区：
文献类型：
--
作者：
Deml, L;Schirmbeck, R;Wagner, R
最近，我们证明了用Epstein-Barr病毒gp220/350衍生的膜锚点取代人类免疫缺陷病毒1型(HIV-1)gp41跨膜蛋白导致嵌合包膜(Env)寡聚体进入Pr55(Gag)病毒样颗粒(VLP)，超过野生型gp160的10倍。在本研究中，我们检测了Pr55(Gag)VLP对(I)嵌合的HIV-1gp120外膜蛋白和(Ii)颗粒外表面的全长gp160的免疫刺激特性。用VLP呈现嵌合型和野生型Enu蛋白的不同衍生物进行的免疫研究，在完全没有额外佐剂的情况下，诱导了一致的抗Pr55(GAG)和抗Env抗体反应。在这两种情况下，免疫血清在MT4细胞中表现出对同源HIV-1感染的体外中和活性，值得注意的是，这些VLP还能够在免疫的BALB/c小鼠中诱导强烈的CD8+细胞毒性T细胞(CTL)反应，该反应针对gp120外糖蛋白第三可变区域V3的已知CTL表位。然而，V3环特异性CTL的诱导严重依赖于Pr55(Gag)VLP提供的Env蛋白的数量。此外，将VLP吸附到明矾上或重复免疫也不会显著改变CD8(+)CTL应答。这些结果表明，Pr55(Gag)VLP提供了一种安全有效的方法来增强对颗粒包裹的gp120蛋白的中和体液反应，并能够将这些蛋白运送到MHC I类抗原处理和递呈途径。因此，抗原扩增的Pr55(Gag)VLP在疫苗设计中是一种有吸引力的方法，需要对复杂糖蛋白产生中和抗体和细胞毒效应功能的特异性刺激。(C)1997年学术出版社。
Very recently, we demonstrated that the replacement of the human immunodeficiency virus type-1 (HIV-1) gp41 transmembrane protein by an Epstein-Barr virus gp220/350-derived membrane anchor resulted in the incorporation of chimeric envelope (Env) oligomers into pr55(gag) virus-like particles (VLPs), exceeding that of wild-type gp160 by a factor of 10, In this study, we examined the immunostimulatory properties of Pr55(gag) VLPs to both (i) chimeric HIV-1 gp120 external envelope proteins and (ii) full-length gp160 presented on the outer surface of the particles. immunization studies carried out with VLPs presenting different derivatives of the chimeric and wild-type Enu proteins elicited a consistent anti-Pr55(gag) as well as anti-Env antibody response in complete absence of additional adjuvants. In both cases, the immune sera exhibited an in vitro neutralizing activity against homologous HIV-1 infection in MT4 cells, Noteworthy, these VLPs were also capable of inducing a strong CD8+ cytotoxic T-cell (CTL) response in immunized BALB/c mice that was directed toward a known CTL epitope in the third variable domain V3 of the gp120 external glycoprotein. However, the induction of V3-loop-specific CTLs critically depended on the amounts of Env proteins that were presented by the Pr55(gag) VLPs. Moreover, the CD8(+) CTL response was not significantly altered by adsorbing the VLPs to alum or by repeated boaster immunizations. These results illustrate that Pr55(gag) VLPS provide a safe and effective means of enhancing neutralizing humoral responses to particle-entrapped gp120 proteins and are also capable of delivering these proteins to the MHC class i antigen processing and presentation pathway. Therefore, antigenically expanded Pr55(gag) VLPS represent an attractive approach in the design of vaccines for which specific stimulation of neutralizing antibodies and cytotoxic effector functions to complex glycoproteins is desired. (C) 1997 Academic Press.