Profiling the Specificity of Neutralizing Antibodies in a Large Panel of Plasmas from Patients Chronically Infected with Human Immunodeficiency Virus Type 1 Subtypes B and C
Profiling the Specificity of Neutralizing Antibodies in a Large Panel of Plasmas from Patients Chronically Infected with Human Immunodeficiency Virus Type 1 Subtypes B and C
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DOI：
10.1128/jvi.01762-08
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发表时间：
2008-12-01
影响因子：
5.4
通讯作者：
Mascola, John R.
中科院分区：
文献类型：
--
作者：
Binley, James M.;Lybarger, Elizabeth A.;Mascola, John R.
鉴定广谱中和抗体（NAb）靶向的病毒表位，有时会在人类免疫缺陷病毒1型（HIV-1）感染的受试者中产生，这将有助于疫苗的设计，以引起类似的反应。在此，我们使用一系列互补作图方法研究了来自亚型B和C感染供体的一组24种广泛中和血浆的活性，主要集中在作为原型亚型B主要分离株的JR-FL上。吸附与固定在珠上的gp 120显示，血浆中和的往往是大的，但可变的分数是针对gp 120，在某些情况下，中和主要是由CD 4结合位点（CD 4 bs）抗体介导的。使用JR-FL三聚体的天然聚丙烯酰胺凝胶电泳测定的结果进一步表明，一半的亚型B和较小部分的亚型C血浆含有显著比例的针对CD 4 b的NAb。在两种亚型的几种血浆中检测到抗gp 41中和活性，但在除一种情况外的所有情况下，仅构成总体中和活性的一小部分。评估亚型B血浆对携带HIV-1 gp 41膜近端外部区域（MPER）各种片段的嵌合HIV-2病毒的活性，发现了混合模式，这意味着MPER中和不受任何类似于已知MPER特异性单克隆抗体的单一特异性支配。V3和2G 12样NAb似乎对JR-FL中和滴度贡献很小或没有贡献。总体而言，我们在几种血浆中观察到抗CD 4 bs NAb的显著滴度，但约三分之二的中和活性仍不确定，表明存在具有特异性的NAb，与迄今为止的任何特征不同。
Identifying the viral epitopes targeted by broad neutralizing antibodies (NAbs) that sometimes develop in human immunodeficiency virus type 1 (HIV-1)-infected subjects should assist in the design of vaccines to elicit similar responses. Here, we investigated the activities of a panel of 24 broadly neutralizing plasmas from subtype B- and C-infected donors using a series of complementary mapping methods, focusing mostly on JR-FL as a prototype subtype B primary isolate. Adsorption with gp120 immobilized on beads revealed that an often large but variable fraction of plasma neutralization was directed to gp120 and that in some cases, neutralization was largely mediated by CD4 binding site (CD4bs) Abs. The results of a native polyacrylamide gel electrophoresis assay using JR-FL trimers further suggested that half of the subtype B and a smaller fraction of subtype C plasmas contained a significant proportion of NAbs directed to the CD4bs. Anti-gp41 neutralizing activity was detected in several plasmas of both subtypes, but in all but one case, constituted only a minor fraction of the overall neutralization activity. Assessment of the activities of the subtype B plasmas against chimeric HIV-2 viruses bearing various fragments of the membrane proximal external region (MPER) of HIV-1 gp41 revealed mixed patterns, implying that MPER neutralization was not dominated by any single specificity akin to known MPER-specific monoclonal Abs. V3 and 2G12-like NAbs appeared to make little or no contribution to JR-FL neutralization titers. Overall, we observed significant titers of anti-CD4bs NAbs in several plasmas, but approximately two-thirds of the neutralizing activity remained undefined, suggesting the existence of NAbs with specificities unlike any characterized to date.