Sharpe Sally, Polyanskaya Natasha, Dennis Mike, Sutter Gerd, Hanke Tomáš, Erfle Volker, Hirsch Vanessa, Cranage Martin
Centre for Applied Microbiology and Research (CAMR), Salisbury SP4 0JG, UK1.
Institut für Molekulare Virologie, GSF-Forschungszentrum für Umwelt und Gesundheit GmbH, Ingolstädter Landstr. 1, 85764 München-Neuherberg, Germany2.
J Gen Virol. 2001 Sep;82(Pt 9):2215-2223. doi: 10.1099/0022-1317-82-9-2215.
A major aim in AIDS vaccine development is the definition of strategies to stimulate strong and durable cytotoxic T lymphocyte (CTL) responses. Here we report that simian immunodeficiency virus (SIV)-specific CTL developed in 4/4 macaques following a single intramuscular injection of modified vaccinia virus Ankara (MVA) constructs expressing both structural and regulatory/accessory genes of SIV. In two animals Nef-specific responses persisted, but other responses diminished and new responses were not revealed, following further vaccination. Vaccination of another two macaques, expressing Mamu A*01 MHC class I, with MVA constructs containing nef and gag-pol under the control of the moderate strength natural vaccinia virus early/late promoter P7.5, again induced an early Nef-specific response, whereas responses to Gag remained undetectable. Anti-vector immunity induced by this immunization was shown to prevent the efficient stimulation of CTL directed to the cognate Gag epitope, p11C C-M, following vaccination with another MVA construct expressing SIV Gag-Pol under a strong synthetic vaccinia virus-specific promoter. In contrast, vaccination of a previously unexposed animal resulted in a SIV-specific CTL response widely disseminated in lymphoid tissues including lymph nodes associated with the rectal and genital routes of SIV entry. Thus, despite the highly attenuated nature of MVA, repeated immunization may elicit sufficient anti-vector immunity to limit the effectiveness of later vaccination.
艾滋病疫苗研发的一个主要目标是确定刺激产生强大且持久的细胞毒性T淋巴细胞（CTL）反应的策略。在此我们报告，在4只猕猴中，单次肌肉注射表达猴免疫缺陷病毒（SIV）结构基因和调节/辅助基因的改良安卡拉痘苗病毒（MVA）构建体后，产生了SIV特异性CTL。在两只动物中，Nef特异性反应持续存在，但进一步接种疫苗后，其他反应减弱且未出现新的反应。用在中等强度天然痘苗病毒早期/晚期启动子P7.5控制下包含nef和gag - pol的MVA构建体对另外两只表达Mamu A*01 MHC I类分子的猕猴进行接种，再次诱导了早期Nef特异性反应，而对Gag的反应仍无法检测到。这种免疫诱导的抗载体免疫被证明可阻止在用另一种在强合成痘苗病毒特异性启动子控制下表达SIV Gag - Pol的MVA构建体接种后，对同源Gag表位p11C C - M的CTL的有效刺激。相比之下，对一只先前未接触过的动物进行接种，导致SIV特异性CTL反应广泛分布于包括与SIV进入的直肠和生殖道相关的淋巴结在内的淋巴组织中。因此，尽管MVA具有高度减毒的特性，但重复免疫可能引发足够的抗载体免疫，从而限制后续接种的效果。
