Kuate Seraphin, Stahl-Hennig Christiane, Stoiber Heribert, Nchinda Godwin, Floto Anja, Franz Monika, Sauermann Ulrike, Bredl Simon, Deml Ludwig, Ignatius Ralf, Norley Steve, Racz Paul, Tenner-Racz Klara, Steinman Ralph M, Wagner Ralf, Uberla Klaus
Department of Molecular and Medical Virology, Ruhr-University Bochum, D-44780 Bochum, Germany.
Virology. 2006 Jul 20;351(1):133-44. doi: 10.1016/j.virol.2006.03.009. Epub 2006 Apr 17.
Vaccination with exogenous antigens such as recombinant viral proteins, immunodeficiency virus-derived whole inactivated virus particles, or virus-like particles (VLP) has generally failed to provide sufficient protection in animal models for AIDS. Pseudotyping VLPs with the vesicular stomatitis virus G protein (VSV-G), which is known to mediate entry into dendritic cells, might allow more efficient stimulation of immune responses. Therefore, we pseudotyped noninfectious immunodeficiency virus-like particles with VSV-G and carried out a preliminary screen of their immunogenicity and vaccination efficacy. Incorporation of VSV-G into HIV-1 VLPs led to hundred-fold higher antibody titers to HIV-1 Gag and enhancement of T cell responses in mice. Repeated vaccination of rhesus monkeys for 65 weeks with VSV-G pseudotyped simian immunodeficiency virus (SIV)-like particles (VLP[G]) provided initial evidence for efficient suppression of viral load after mucosal challenge with the SIVmac239 virus. Challenge of monkeys after a 28 week vaccination regimen with VLP[G] led to a reduction in peak viremia, but persistent suppression of viral load was not achieved. Due to limitations in the number of animals available for this study, improved efficacy of VSV-G pseudotyped VLPs in nonhuman primates could not be demonstrated. However, mouse experiments revealed that pseudotyping of VLPs with fusion-competent VSV-G clearly improves their immunogenicity. Additional strategies, particularly adjuvants, should be considered to provide greater protection against a challenge with pathogenic immunodeficiency virus.
用重组病毒蛋白、免疫缺陷病毒来源的全灭活病毒颗粒或病毒样颗粒（VLP）等外源性抗原进行疫苗接种，在艾滋病动物模型中通常未能提供足够的保护。用已知可介导进入树突状细胞的水疱性口炎病毒G蛋白（VSV-G）对VLP进行假型化，可能会更有效地刺激免疫反应。因此，我们用VSV-G对非感染性免疫缺陷病毒样颗粒进行假型化，并对其免疫原性和疫苗接种效果进行了初步筛选。将VSV-G掺入HIV-1 VLP中，导致小鼠体内针对HIV-1 Gag的抗体滴度提高了百倍，并增强了T细胞反应。用VSV-G假型化的猿猴免疫缺陷病毒（SIV）样颗粒（VLP[G]）对恒河猴进行65周的重复疫苗接种，为在黏膜感染SIVmac239病毒后有效抑制病毒载量提供了初步证据。在28周的疫苗接种方案后用VLP[G]对猴子进行攻击，导致病毒血症峰值降低，但未实现对病毒载量的持续抑制。由于本研究可用动物数量有限，无法证明VSV-G假型化VLP在非人灵长类动物中的疗效有所提高。然而，小鼠实验表明，用具有融合能力的VSV-G对VLP进行假型化明显提高了它们的免疫原性。应考虑采用其他策略，特别是佐剂，以提供更大的保护，抵御致病性免疫缺陷病毒的攻击。
