Chackerian Bryce, Briglio Lindsey, Albert Paul S, Lowy Douglas R, Schiller John T
Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Virol. 2004 Apr;78(8):4037-47. doi: 10.1128/jvi.78.8.4037-4047.2004.
Antibodies against CCR5, the major coreceptor for human immunodeficiency virus type 1 (HIV-1), may have antiviral potential as viral fusion inhibitors. In this study, we generated a virus-like particle (VLP)-based vaccine that effectively breaks B-cell tolerance and elicits autoantibodies against CCR5 in pig-tailed macaques. Initial studies in mice identified a polypeptide comprising the N-terminal domain of pig-tailed macaque CCR5 fused to streptavidin that, when conjugated at high density to bovine papillomavirus major capsid protein L1 VLPs, induced high-titer immunoglobulin G (IgG) that bound to a macaque CCR5-expressing cell line in vitro. In macaques, CCR5 peptide-conjugated VLP preparations induced high-avidity anti-CCR5 IgG autoantibody responses, and all five immunized macaques generated IgG that could block infection of CCR5-tropic simian/human immunodeficiency virus SHIV(SF162P3) in vitro. Although the anti-CCR5 IgG titers declined with time, autoantibody levels were boosted upon revaccination. Vaccinated macaques remained healthy for a period of over 3 years after the initial immunization, and no decline in the number of CCR5-expressing T cells was detected. To test the prophylactic efficacy of CCR5 autoantibodies, immunized macaques were challenged with SHIV(SF162P3). Although the plasma-associated virus in half of six control macaques declined to undetectable levels, viral loads were lower, declined more rapidly, and eventually became undetectable in all five macaques in which CCR5 autoantibodies had been elicited. In addition, in the four vaccinated macaques with higher autoantibody titers, viral loads and time to control of viremia were significantly decreased relative to controls, indicating the possibility that CCR5 autoantibodies contributed to the control of viral replication.
针对人免疫缺陷病毒1型（HIV-1）主要共受体CCR5的抗体，作为病毒融合抑制剂可能具有抗病毒潜力。在本研究中，我们制备了一种基于病毒样颗粒（VLP）的疫苗，该疫苗能有效打破B细胞耐受性，并在食蟹猴体内引发抗CCR5自身抗体。最初在小鼠中的研究鉴定出一种由与链霉亲和素融合的食蟹猴CCR5 N端结构域组成的多肽，当该多肽以高密度偶联到牛乳头瘤病毒主要衣壳蛋白L1 VLP上时，可诱导出在体外与表达食蟹猴CCR5的细胞系结合的高滴度免疫球蛋白G（IgG）。在食蟹猴中，CCR5肽偶联的VLP制剂诱导了高亲和力的抗CCR5 IgG自身抗体反应，所有五只免疫的食蟹猴均产生了能在体外阻断CCR5嗜性猿猴/人类免疫缺陷病毒SHIV(SF162P3)感染的IgG。尽管抗CCR5 IgG滴度随时间下降，但再次接种疫苗后自身抗体水平得到提高。接种疫苗的食蟹猴在初次免疫后超过3年的时间里保持健康，未检测到表达CCR5的T细胞数量减少。为了测试CCR5自身抗体的预防效果，用SHIV(SF162P3)对免疫的食蟹猴进行攻击。虽然六只对照食蟹猴中有一半的血浆相关病毒下降到无法检测的水平，但在所有五只产生CCR5自身抗体的食蟹猴中，病毒载量更低、下降更快，最终变得无法检测。此外，在四只自身抗体滴度较高的接种食蟹猴中，相对于对照，病毒载量和病毒血症得到控制的时间显著缩短，这表明CCR5自身抗体可能有助于控制病毒复制。
