Selection pressure from neutralizing antibodies drives sequence evolution during acute infection with hepatitis C virus.
Selection pressure from neutralizing antibodies drives sequence evolution during acute infection with hepatitis C virus.
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DOI：
10.1053/j.gastro.2009.02.080
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发表时间：
2009-06
期刊：
影响因子：
29.4
通讯作者：
Ray SC
中科院分区：
文献类型：
--
作者：
Dowd KA;Netski DM;Wang XH;Cox AL;Ray SC
尽管最近对丙型肝炎病毒特异性中和抗体进行了表征，但尚不清楚中和抗体的免疫压力在多大程度上驱动体内病毒序列进化。这种缺乏理解在急性感染中尤其明显，在急性感染阶段，病毒复制的消除或持续已被确定，在此阶段，体液免疫反应的重要性已被大大低估。我们分析了八个个体在整个急性感染过程中的包膜糖蛋白序列进化和连续自体丙型肝炎病毒假颗粒的中和。氨基酸取代发生在整个包膜基因中，主要是在 E2 的高变区 1 内。当使用表达连续包膜序列的个体化假颗粒来测量自体血清的中和作用时，中和较早序列变体的抗体比中和较晚变体的抗体在更早的时间点被检测到，这表明病毒变体响应于中和抗体的压力而被清除和进化。为了证明氨基酸取代对中和的影响，假粒子包膜序列的定点诱变揭示了高变区 1 中的氨基酸取代，这导致中和敏感性随着时间的推移急剧下降。此外，高滴度中和抗体在所有自发解析器中的病毒清除时达到峰值，而长期进化的受试者在整个早期急性感染期间表现出低滴度或缺乏中和抗体。这些发现表明，在体内急性丙型肝炎病毒感染期间，病毒特异性中和抗体驱动序列进化，并且在某些个体中，在确定感染结果中发挥作用。
Despite recent characterization of hepatitis C virus-specific neutralizing antibodies, it is not clear to what extent immune pressure from neutralizing antibodies drives viral sequence evolution in vivo. This lack of understanding is particularly evident in acute infection, the phase when elimination or persistence of viral replication is determined and during which the importance of the humoral immune response has been largely discounted. We analyzed envelope glycoprotein sequence evolution, and neutralization of sequential autologous hepatitis C virus pseudoparticles in eight individuals throughout acute infection. Amino acid substitutions occurred throughout the envelope genes, primarily within the hypervariable region 1 of E2. When individualized pseudoparticles expressing sequential envelope sequences were used to measure neutralization by autologous sera, antibodies neutralizing earlier sequence variants were detected at earlier time points than antibodies neutralizing later variants, indicating clearance and evolution of viral variants in response to pressure from neutralizing antibodies. To demonstrate the effects of amino acid substitution on neutralization, site-directed mutagenesis of a pseudoparticle envelope sequence revealed amino acid substitutions in hypervariable region 1 that were responsible for a dramatic decrease in neutralization sensitivity over time. In addition, high-titer neutralizing antibodies peaked at the time of viral clearance in all spontaneous resolvers, while chronically evolving subjects displayed low-titer or absent neutralizing antibodies throughout early acute infection. These findings indicate that during acute hepatitis C virus infection in vivo, virus-specific neutralizing antibodies drive sequence evolution and, in some individuals, play a role in determining the outcome of infection.
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DOI：
10.1084/jem.20050121
发表时间：
2005-06-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cox AL;Mosbruger T;Mao Q;Liu Z;Wang XH;Yang HC;Sidney J;Sette A;Pardoll D;Thomas DL;Ray SC
通讯作者：
Ray SC
影响因子：
158.5
作者：
Alter, MJ;Kruszon-Moran, D;Margolis, HS
通讯作者：
Margolis, HS
影响因子：
5.4
作者：
Lavillette, D;Morice, Y;Cosset, FL
通讯作者：
Cosset, FL
影响因子：
5.4
作者：
Keck, Zhen-Yong;Li, Ta-Kai;Foung, Steven K. H.
通讯作者：
Foung, Steven K. H.
影响因子：
29.4
作者：
Lauer, GM;Barnes, E;Klenerman, P
通讯作者：
Klenerman, P