The B Cell Response Is Redundant and Highly Focused on V1V2 during Early Subtype C Infection in a Zambian Seroconverter
The B Cell Response Is Redundant and Highly Focused on V1V2 during Early Subtype C Infection in a Zambian Seroconverter
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DOI：
10.1128/jvi.02006-10
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发表时间：
2011-01-01
影响因子：
5.4
通讯作者：
Derdeyn, Cynthia A.
中科院分区：
文献类型：
--
作者：
Lynch, Rebecca M.;Rong, Rong;Derdeyn, Cynthia A.
在早期感染C亚型人类免疫缺陷病毒1型(HIV-1)期间，已经证实了高滴度的自体中和抗体反应。然而，在单抗水平上对自体病毒的这种反应的特征直到最近才开始被阐明。在这里，我们描述了来自C亚型感染血清转换者的五种单抗，以及它们在估计感染时间后48天(0个月)、2个月和8个月对携带包膜糖蛋白的伪病毒的中和活性。序列分析表明，这些单抗来自三个不同的B细胞克隆，它们的中和模式与患者血浆中的中和模式相比较，表明它们在感染后2至8个月之间循环。代表每个B细胞克隆的单抗的中和被映射到两个残基：V1中的134位和V2中的189位。突变分析揭示了这两个位置的糖链和残基之间的协同效应，认为它们构成了单一的表位。通过同源建模对同源gp120序列的分析将该潜在表位放置在V1和V2环之间的界面附近。此外，V2中的逃逸突变R189S对所有三种单抗都具有抵抗力，对病毒的体外复制没有不利影响。综上所述，我们的数据表明，在早期感染期间，独立的B细胞重复地针对V1V2中的单一结构。尽管有这样的攻击，一个单一的氨基酸变化就足以完全逃脱，而对复制适应性的影响最小。
High-titer autologous neutralizing antibody responses have been demonstrated during early subtype C human immunodeficiency virus type 1 (HIV-1) infection. However, characterization of this response against autologous virus at the monoclonal antibody (MAb) level has only recently begun to be elucidated. Here we describe five monoclonal antibodies derived from a subtype C-infected seroconverter and their neutralizing activities against pseudoviruses that carry envelope glycoproteins from 48 days (0 month), 2 months, and 8 months after the estimated time of infection. Sequence analysis indicated that the MAbs arose from three distinct B cell clones, and their pattern of neutralization compared to that in patient plasma suggested that they circulated between 2 and 8 months after infection. Neutralization by MAbs representative of each B cell clone was mapped to two residues: position 134 in V1 and position 189 in V2. Mutational analysis revealed cooperative effects between glycans and residues at these two positions, arguing that they contribute to a single epitope. Analysis of the cognate gp120 sequence through homology modeling places this potential epitope near the interface between the V1 and V2 loops. Additionally, the escape mutation R189S in V2, which conferred resistance against all three MAbs, had no detrimental effect on virus replication in vitro. Taken together, our data demonstrate that independent B cells repeatedly targeted a single structure in V1V2 during early infection. Despite this assault, a single amino acid change was sufficient to confer complete escape with minimal impact on replication fitness.