Persistence of Circulating Memory B Cell Clones with Potential for Dengue Virus Disease Enhancement for Decades following Infection

被引:118
作者
Smith, Scott A. [2 ,6 ]
Zhou, Yang [7 ]
Olivarez, Nicholas P. [7 ]
Broadwater, Anne H. [7 ]
de Silva, Aravinda M. [7 ]
Crowe, James E., Jr. [1 ,3 ,4 ,5 ,6 ]
机构
[1] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA
[4] Vanderbilt Univ, Med Ctr, Dept Microbiol, Nashville, TN 37232 USA
[5] Vanderbilt Univ, Med Ctr, Dept Immunol, Nashville, TN 37232 USA
[6] Vanderbilt Univ, Med Ctr, Vanderbilt Vaccine Ctr, Nashville, TN 37232 USA
[7] Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA
关键词
WEST-NILE-VIRUS; ANTIBODY-DEPENDENT ENHANCEMENT; TYPE-2 ENVELOPE PROTEIN; DOMAIN-III; MONOCLONAL-ANTIBODIES; MEDIATED NEUTRALIZATION; CRYSTAL-STRUCTURE; BINDING; GLYCOPROTEIN; RECOGNITION;
D O I
10.1128/JVI.06335-11
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Symptomatic dengue virus infection ranges in disease severity from an influenza-like illness to life-threatening shock. One model of the mechanism underlying severe disease proposes that weakly neutralizing, dengue serotype cross-reactive antibodies induced during a primary infection facilitate virus entry into Fc receptor-bearing cells during a subsequent secondary infection, increasing viral replication and the release of cytokines and vasoactive mediators, culminating in shock. This process has been termed antibody-dependent enhancement of infection and has significantly hindered vaccine development. Much of our understanding of this process has come from studies using mouse monoclonal antibodies (MAbs); however, antibody responses in mice typically exhibit less complexity than those in humans. A better understanding of the humoral immune response to natural dengue virus infection in humans is sorely needed. Using a high-efficiency human hybridoma technology, we isolated 37 hybridomas secreting human MAbs to dengue viruses from 12 subjects years or even decades following primary or secondary infection. The majority of the human antibodies recovered were broadly cross-reactive, directed against either envelope or premembrane proteins, and capable of enhancement of infection in vitro; few exhibited serotype-specific binding or potent neutralizing activity. Memory B cells encoding enhancing antibodies predominated in the circulation, even two or more decades following infection. Mapping the epitopes and activity of naturally occurring dengue antibodies should prove valuable in determining whether the enhancing and neutralizing activity of antibodies can be separated. Such principles could be used in the rational design of vaccines that enhance the induction of neutralizing antibodies, while lowering the risk of dengue shock syndrome.
引用
收藏
页码:2665 / 2675
页数:11
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