Ancestral and consensus envelope immunogens for HIV-1 subtype C
Ancestral and consensus envelope immunogens for HIV-1 subtype C
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DOI：
10.1016/j.virol.2006.05.011
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发表时间：
2006-09-01
期刊：
影响因子：
3.7
通讯作者：
Hahn, Beatrice H.
中科院分区：
文献类型：
--
作者：
Kothe, Denise L.;Li, Yingying;Hahn, Beatrice H.
基于“集中”（祖先或共有）HIV-1序列的免疫原最大限度地缩短了疫苗株与当代病毒之间的遗传距离，因此应能引发识别更广泛病毒变体的免疫反应。然而，此类推断基因产物的生物学、抗原性和免疫原性特性必须经过实验验证。在这里，我们报告了 HIV-1（M 组）C 亚型的第一个全长祖先（AncC）和共有（ConC）env 基因的构建和表征。密码子使用优化的基因表达高水平的包膜糖蛋白，这些糖蛋白掺入 HIV-1 病毒颗粒中，通过 CCR5 辅助受体介导感染，并保留慢性 HIV-1 C 亚型感染患者血浆所识别的中和表位。用AncC和ConC env DNA免疫的豚鼠产生高滴度结合，但没有明显的同源或异源中和抗体。通过免疫印迹分析进行测试时，来自 AncC 和 ConC env 免疫的豚鼠的血清比来自用当代 C 亚型 env 对照免疫的豚鼠的血清识别出更多数量的初级 C 亚型包膜糖蛋白。用AncC和ConC env DNA免疫的小鼠产生了γ干扰素T细胞反应，该反应识别来自同源ConC和异源亚型C Env对照的重叠肽。因此，AncC 和 ConC env 基因都表达功能性包膜糖蛋白，这些糖蛋白在实验动物中具有免疫原性，并引发具有相当广度和强度的体液和细胞免疫反应。这些结果确立了集中式 HIV-1 C 亚型 Env 免疫原的效用，并保证将其作为未来艾滋病疫苗的潜在成分进行持续评估。 (c) 2006 Elsevier Inc. 保留所有权利。
Immunogens based on "centralized" (ancestral or consensus) HIV-1 sequences minimize the genetic distance between vaccine strains and contemporary viruses and should thus elicit immune responses that recognize a broader spectrum of viral variants. However, the biologic, antigenic and immunogenic properties of such inferred gene products have to be validated experimentally. Here, we report the construction and characterization of the first full-length ancestral (AncC) and consensus (ConC) env genes of HIV-1 (group M) subtype C. The codon-usage-optimized genes expressed high levels of envelope glycoproteins that were incorporated into HIV-1 virions, mediated infection via the CCR5 coreceptor and retained neutralizing epitopes as recognized by plasma from patients with chronic HIV-1 subtype C infection. Guinea pigs immunized with AncC and ConC env DNA developed high titer binding, but no appreciable homologous or heterologous neutralizing antibodies. When tested by immunoblot analysis, sera from AncC and ConC env immunized guinea pigs recognized a greater number of primary subtype C envelope glycoproteins than sera from guinea pigs immunized with a contemporary subtype C env control. Mice immunized with AncC and ConC env DNA developed gamma interferon T cell responses that recognized overlapping peptides from the cognate ConC and a heterologous subtype C Env control. Thus, both AncC and ConC env genes expressed functional envelope glycoproteins that were immunogenic in laboratory animals and elicited humoral and cellular immune responses of comparable breadth and magnitude. These results establish the utility of centralized HIV-1 subtype C Env immunogens and warrant their continued evaluation as potential components of future AIDS vaccines. (c) 2006 Elsevier Inc. All rights reserved.