Phenotypic deficits in the HIV-1 envelope are associated with the maturation of a V2-directed broadly neutralizing antibody lineage
Phenotypic deficits in the HIV-1 envelope are associated with the maturation of a V2-directed broadly neutralizing antibody lineage
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HIV-1 包膜的表型缺陷与 V2 导向的广泛中和抗体谱系的成熟相关
作者：
L. Reh;Carsten Magnus;C. Kadelka;D. Kühnert;T. Uhr;J. Weber;L. Morris;P. Moore;A. Trkola
HIV-1的广谱中和抗体(BNAbs)可以在多年的病毒逃逸和抗体适应的迭代过程中进化，HIV-1疫苗的设计试图模仿这种过程。要实现这一点，需要定义使HIV-1信封(Env)能够引发bNab应答的属性。在这里，我们跟踪了HIV-1 C亚型重叠感染供体CAP256中V2顶点定向的bNab谱系VRC26的进化，以研究在bNab诱导之前和早期阶段循环中病毒群体的表型变化。从VRC26抗性的初级感染(PI)病毒、VRC26敏感的超级感染(SU)病毒以及随后的PI-SU重组体进化而来的纵向病毒显示了Env的实质性表型变化，Env特性的转换与VRC26的早期抗性相吻合。SU类病毒对VRC26的敏感性降低与感染性降低、进入动力学改变以及CD4附着后对中和的敏感性降低有关。VRC26对细胞相关的CAP256病毒保持中和活性，表明通过细胞-细胞传递途径逃逸不是主要的逃逸途径。早期逃逸变异体的适合性降低和细胞间传播的持续敏感性都限制了病毒的复制，从而阻碍了快速逃逸。这支持一种情况，即VRC26在很长一段时间内只允许部分病毒逃逸，可能会增加bNab成熟的时间窗口。总而言之，我们的数据强调了HIV-1Env在逃避bNab压力方面的表型可塑性，以及在选择和设计Env免疫原时需要考虑表型特征。具有不同表型模式和bNab敏感性的env变体的组合，就像我们在这里为CAP256所描述的那样，可能会最大限度地通过疫苗接种来诱导bNab反应。
Broadly neutralizing antibodies (bnAbs) to HIV-1 can evolve after years of an iterative process of virus escape and antibody adaptation that HIV-1 vaccine design seeks to mimic. To enable this, properties that render HIV-1 envelopes (Env) capable of eliciting bnAb responses need to be defined. Here, we followed the evolution of the V2 apex directed bnAb lineage VRC26 in the HIV-1 subtype C superinfected donor CAP256 to investigate the phenotypic changes of the virus populations circulating before and during the early phases of bnAb induction. Longitudinal viruses that evolved from the VRC26-resistant primary infecting (PI) virus, the VRC26-sensitive superinfecting (SU) virus and ensuing PI-SU recombinants revealed substantial phenotypic changes in Env, with a switch in Env properties coinciding with early resistance to VRC26. Decreased sensitivity of SU-like viruses to VRC26 was linked with reduced infectivity, altered entry kinetics and lower sensitivity to neutralization after CD4 attachment. VRC26 maintained neutralization activity against cell-associated CAP256 virus, indicating that escape through the cell-cell transmission route is not a dominant escape pathway. Reduced fitness of the early escape variants and sustained sensitivity in cell-cell transmission are both features that limit virus replication, thereby impeding rapid escape. This supports a scenario where VRC26 allowed only partial viral escape for a prolonged period, possibly increasing the time window for bnAb maturation. Collectively, our data highlight the phenotypic plasticity of the HIV-1 Env in evading bnAb pressure and the need to consider phenotypic traits when selecting and designing Env immunogens. Combinations of Env variants with differential phenotypic patterns and bnAb sensitivity, as we describe here for CAP256, may maximize the potential for inducing bnAb responses by vaccination.
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影响因子：
30.3
作者：
Haynes BF;Shaw GM;Korber B;Kelsoe G;Sodroski J;Hahn BH;Borrow P;McMichael AJ
通讯作者：
McMichael AJ
影响因子：
32.4
作者：
Locci M;Havenar-Daughton C;Landais E;Wu J;Kroenke MA;Arlehamn CL;Su LF;Cubas R;Davis MM;Sette A;Haddad EK;International AIDS Vaccine Initiative Protocol C Principal Investigators;Poignard P;Crotty S
通讯作者：
Crotty S
影响因子：
7
作者：
Walker LM;Burton DR
通讯作者：
Burton DR
影响因子：
29.7
作者：
Burton DR;Hangartner L
通讯作者：
Hangartner L
DOI：
10.1056/nejmoa1608243
发表时间：
2016-11-24
期刊：
The New England journal of medicine
影响因子：
--
作者：
Bar KJ;Sneller MC;Harrison LJ;Justement JS;Overton ET;Petrone ME;Salantes DB;Seamon CA;Scheinfeld B;Kwan RW;Learn GH;Proschan MA;Kreider EF;Blazkova J;Bardsley M;Refsland EW;Messer M;Clarridge KE;Tustin NB;Madden PJ;Oden K;O'Dell SJ;Jarocki B;Shiakolas AR;Tressler RL;Doria-Rose NA;Bailer RT;Ledgerwood JE;Capparelli EV;Lynch RM;Graham BS;Moir S;Koup RA;Mascola JR;Hoxie JA;Fauci AS;Tebas P;Chun TW
通讯作者：
Chun TW