Shata Mohamed Tarek M, Pfahler Wolfram, Brotman Betsy, Lee Dong-Hun, Tricoche Nancy, Murthy Krishna, Prince Alfred M
Laboratory of Virology, Lindsley F. Kimball Research Institute of the New York Blood Center, New York, NY 10021, USA.
J Med Primatol. 2006 Jun;35(3):165-71. doi: 10.1111/j.1600-0684.2006.00152.x.
We previously reported successful therapeutic immunization in a chimpanzee having a relatively low viral load, which was immunized with recombinant plasmid hepatitis B surface antigen (HBsAg) DNA and boosted with recombinant HBsAg encoding canarypox virus. In the present study, we attempted to confirm these findings in an animal with a high virus load.
We tested three immunization strategies successively over a 3-year period. In the first of these, we administered four monthly injections of DNA encoding HBsAg + PreS2 + hepatitis B core antigen (HBcAg) + DNA encoding interleukin (IL)-12, (given 3 days later), and boosted with canarypox expressing all of the above HBV genes 6 months after initial immunization. No reduction in viral load was observed. In the second trial, we administered lamivudine for 8 weeks, and then began monthly DNA-based immunization with plasmids expressing the above viral genes; however, viral loads rebounded 1 week after termination of lamivudine therapy. In a third trial, we continued lamivudine therapy for 30 weeks and immunized with vaccinia virus expressing the above viral genes 18 and 23 weeks after the start of lamivudine therapy. Again viral loads rebounded shortly after cessation of lamivudine treatment. Analysis of cell-mediated immune responses, and their avidity, revealed that DNA-based immunization produced the strongest enhancement of high avidity T-cell responses, while recombinant vaccinia immunization during lamivudine therapy enhanced low avidity responses only. The strongest low and high avidity responses were directed to the middle surface antigen.
Three strategies for therapeutic immunization failed to control HBV viremia in a chronically infected chimpanzee with a high viral load.
我们之前报道了在一只病毒载量相对较低的黑猩猩身上成功进行治疗性免疫的案例，该黑猩猩用重组质粒乙型肝炎表面抗原（HBsAg）DNA进行免疫，并以表达HBsAg的金丝雀痘病毒进行加强免疫。在本研究中，我们试图在一只病毒载量高的动物身上证实这些发现。
我们在3年时间里相继测试了三种免疫策略。在第一种策略中，我们每月注射4次编码HBsAg + 前S2 + 乙型肝炎核心抗原（HBcAg）的DNA + 编码白细胞介素（IL）-12的DNA（3天后注射），并在初次免疫6个月后用表达上述所有乙肝病毒基因的金丝雀痘病毒进行加强免疫。未观察到病毒载量降低。在第二项试验中，我们给予拉米夫定治疗8周，然后开始每月用表达上述病毒基因的质粒进行基于DNA的免疫；然而，拉米夫定治疗终止1周后病毒载量反弹。在第三项试验中，我们继续拉米夫定治疗30周，并在拉米夫定治疗开始18周和23周后用表达上述病毒基因的痘苗病毒进行免疫。拉米夫定治疗停止后不久病毒载量再次反弹。对细胞介导的免疫反应及其亲和力的分析表明，基于DNA的免疫产生了高亲和力T细胞反应的最强增强，而在拉米夫定治疗期间进行重组痘苗免疫仅增强了低亲和力反应。最强的低亲和力和高亲和力反应针对中表面抗原。
三种治疗性免疫策略未能控制一只病毒载量高的慢性感染黑猩猩的乙肝病毒血症。
