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High-Resolution Sequencing of Viral Populations during Early Simian Immunodeficiency Virus Infection Reveals Evolutionary Strategies for Rapid Escape from Emerging Env-Specific Antibody Responses
Journal of Virology ( IF 5.4 ) Pub Date : 2018-04-01 , DOI: 10.1128/jvi.01574-17
Sergio Ita 1, 2 , Alison K. Hill 1, 2 , Evan C. Lam 2 , Fay J. Dufort 2 , Xiao Yang 3 , Ruchi Newman 3 , Sivan Leviyang 4 , Ismael B. Fofana 2 , Welkin E. Johnson 2
Affiliation  

Primate lentiviruses, including the human and simian immunodeficiency viruses (HIV and SIV), produce infections marked by persistent, ongoing viral replication. This occurs despite the presence of virus-specific adaptive immune responses, including antibodies targeting the viral envelope glycoprotein (Env), and evolution of antibody-escape variants is a well-documented feature of lentiviral infection. Here, we examined the evolutionary dynamics of the SIV env gene during early infection (≤29 weeks postinfection) in a cohort of four SIVmac251-infected rhesus macaques. We tracked env evolution during acute and early infection using frequent sampling and ultradeep sequencing of viral populations, capturing a transmission bottleneck and the subsequent reestablishment of Env diversity. A majority of changes in the gp120 subunit mapped to two short clusters, one in the first variable region (V1) and one in V4, while most changes in the gp41 subunit appeared in the cytoplasmic domain. Variation in V1 was dominated by short duplications and deletions of repetitive sequence, while variation in V4 was marked by short in-frame deletions and closely overlapping substitutions. The most common substitutions in both patches did not alter viral replicative fitness when tested using a highly sensitive, deep-sequencing-based competition assay. Our results, together with the observation that very similar or identical patterns of sequence evolution also occur in different macaque species infected with related but divergent strains of SIV, suggest that resistance to early, strain-specific anti-Env antibodies is the result of temporally and mutationally predictable pathways of escape that occur during the early stages of infection.

IMPORTANCE The envelope glycoprotein (Env) of primate lentiviruses mediates entry by binding to host cell receptors followed by fusion of the viral membrane with the cell membrane. The exposure of Env complexes on the surface of the virion results in targeting by antibodies, leading to selection for virus escape mutations. We used the SIV/rhesus macaque model to track in vivo evolution of variation in Env during acute/early infection in animals with and without antibody responses to Env, uncovering remarkable variation in animals with antibody responses within weeks of infection. Using a deep-sequencing-based fitness assay, we found substitutions associated with antibody escape had little to no effect on inherent replicative capacity. The ability to readily propagate advantageous changes that incur little to no replicative fitness costs may be a mechanism to maintain continuous replication under constant immune selection, allowing the virus to persist for months to years in the infected host.



中文翻译:

早期猿猴免疫缺陷病毒感染期间病毒种群的高分辨率测序揭示了从新兴的环境特异性抗体反应中快速逃脱的进化策略。

灵长类慢病毒,包括人类和猿猴免疫缺陷病毒(HIV和SIV),会产生以持续不断的病毒复制为特征的感染。尽管存在病毒特异性的适应性免疫反应,包括靶向病毒包膜糖蛋白(Env)的抗体,但仍会发生这种情况,抗体逃逸变体的进化是慢病毒感染的一个有据可查的特征。在这里,我们研究了在四个感染SIV mac 251的恒河猴的队列中,在早期感染(感染后≤29周)期间SIV env基因的进化动力学。我们跟踪的ENV使用病毒种群的频繁采样和超深度测序在急性和早期感染过程中进行进化,捕获传播瓶颈并随后重新建立Env多样性。gp120亚基的大部分变化都映射到两个短簇,一个在第一可变区(V1)中,一个在V4中,而gp41亚基的大多数变化都出现在细胞质域中。V1的变异以重复序列的短重复和缺失为主导,而V4的变异以短框内缺失和紧密重叠的替代为特征。当使用高度敏感的,基于深度测序的竞争测定法进行测试时,两个补丁中最常见的替代都不会改变病毒的复制适应性。我们的结果

重要灵长类慢病毒的包膜糖蛋白(Env)通过与宿主细胞受体结合,然后病毒膜与细胞膜融合来介导进入。Env复合物在病毒粒子表面的暴露导致抗体靶向,从而导致选择病毒逃逸突变。我们使用了SIV / rhesus猕猴模型来追踪体内在有或没有针对Env的抗体反应的动物的急性/早期感染过程中,Env变异的变化,揭示了在感染后数周内具有抗体反应的动物的显着变化。使用基于深度测序的适应性分析,我们发现与抗体逃逸相关的取代对固有复制能力几乎没有影响。能够轻易传播有益变化的能力几乎不会产生复制适应性费用,这可能是一种在恒定免疫选择下保持连续复制的机制,从而使病毒在感染宿主中可以持续数月至数年。

更新日期:2018-03-15
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