Stamatos N M, Mascola J R, Kalyanaraman V S, Louder M K, Frampton L M, Birx D L, VanCott T C
Division of Retrovirology, Walter Reed Army Institute of Research, Rockville, Maryland 20850, USA.
J Virol. 1998 Dec;72(12):9656-67. doi: 10.1128/JVI.72.12.9656-9667.1998.
Antibodies that neutralize primary isolates of human immunodeficiency virus type 1 (HIV-1) appear during HIV-1 infection but are difficult to elicit by immunization with current vaccine products comprised of monomeric forms of HIV-1 envelope glycoprotein gp120. The limited neutralizing antibody response generated by gp120 vaccine products could be due to the absence or inaccessibility of the relevant epitopes. To determine whether neutralizing antibodies from HIV-1-infected patients bind to epitopes accessible on monomeric gp120 and/or oligomeric gp140 (ogp140), purified total immunoglobulin from the sera of two HIV-1-infected patients as well as pooled HIV immune globulin were selectively depleted of antibodies which bound to immobilized gp120 or ogp140. After passage of each immunoglobulin preparation through the respective columns, antibody titers against gp120 and ogp140 were specifically reduced at least 128-fold. The gp120- and gp140-depleted antibody fraction from each serum displayed reduced neutralization activity against three primary and two T-cell line-adapted (TCLA) HIV-1 isolates. Significant residual neutralizing activity, however, persisted in the depleted sera, indicating additional neutralizing antibody specificities. gp120- and ogp140-specific antibodies eluted from each column neutralized both primary and TCLA viruses. These data demonstrate the presence and accessibility of epitopes on both monomeric gp120 and ogp140 that are specific for antibodies that are capable of neutralizing primary isolates of HIV-1. Thus, the difficulties associated with eliciting neutralizing antibodies by using current monomeric gp120 subunit vaccines may be related less to improper protein structure and more to ineffective immunogen formulation and/or presentation.
在人类免疫缺陷病毒1型（HIV-1）感染过程中会出现中和HIV-1原始分离株的抗体，但用目前由HIV-1包膜糖蛋白gp120单体形式组成的疫苗产品进行免疫接种很难诱发此类抗体。gp120疫苗产品产生的中和抗体反应有限，可能是由于相关表位不存在或无法接近。为了确定来自HIV-1感染患者的中和抗体是否与单体gp120和/或寡聚体gp140（ogp140）上可接近的表位结合，从两名HIV-1感染患者的血清中纯化的总免疫球蛋白以及汇集的HIV免疫球蛋白被选择性去除与固定化gp120或ogp140结合的抗体。每种免疫球蛋白制剂通过各自的柱子后，针对gp120和ogp140的抗体滴度特异性降低了至少128倍。每种血清中去除gp120和gp140的抗体部分对三种原始和两种T细胞系适应（TCLA）HIV-1分离株的中和活性降低。然而，在去除抗体的血清中仍存在显著的残余中和活性，表明存在其他中和抗体特异性。从每个柱子上洗脱的gp120和ogp140特异性抗体中和了原始病毒和TCLA病毒。这些数据证明了单体gp120和ogp140上存在对能够中和HIV-1原始分离株的抗体具有特异性的表位，并且这些表位是可接近的。因此，使用目前的单体gp120亚单位疫苗诱发中和抗体的困难可能与蛋白质结构不当关系较小，而与免疫原制剂和/或呈递无效关系更大。
