Ita Sergio, Hill Alison K, Lam Evan C, Dufort Fay J, Yang Xiao, Newman Ruchi, Leviyang Sivan, Fofana Ismael B, Johnson Welkin E
Virology Program, Harvard Medical School, Boston, Massachusetts, USA.
Department of Biology, Boston College, Chestnut Hill, Massachusetts, USA.
J Virol. 2018 Mar 14;92(7). doi: 10.1128/JVI.01574-17. Print 2018 Apr 1.
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 gene during early infection (≤29 weeks postinfection) in a cohort of four SIV251-infected rhesus macaques. We tracked 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. 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 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.
灵长类慢病毒，包括人类免疫缺陷病毒（HIV）和猴免疫缺陷病毒（SIV），会引发以持续性病毒复制为特征的感染。尽管存在病毒特异性适应性免疫反应，包括针对病毒包膜糖蛋白（Env）的抗体，但这种持续性病毒复制仍会发生，而抗体逃逸变体的进化是慢病毒感染的一个有充分记录的特征。在此，我们研究了4只感染SIV251的恒河猴群体在早期感染（感染后≤29周）期间SIV基因的进化动态。我们通过对病毒群体进行频繁采样和超深度测序来追踪急性感染期和早期感染期的进化情况，捕捉到了一个传播瓶颈以及随后Env多样性的重新建立。gp120亚基的大多数变化定位于两个短簇，一个在第一个可变区（V1），另一个在V4，而gp41亚基的大多数变化出现在细胞质结构域。V1区的变异主要由重复序列的短片段重复和缺失主导，而V4区的变异则以短的框内缺失和紧密重叠的替换为特征。当使用基于深度测序的高灵敏度竞争试验进行测试时，这两个区域最常见的替换对病毒的复制适应性没有影响。我们的研究结果，以及在感染相关但不同毒株的不同猕猴物种中也出现非常相似或相同的序列进化模式这一观察结果，表明对早期、毒株特异性抗Env抗体的抗性是感染早期阶段发生的时间上和突变上可预测的逃逸途径的结果。灵长类慢病毒的包膜糖蛋白（Env）通过与宿主细胞受体结合，随后使病毒膜与细胞膜融合来介导病毒进入。病毒粒子表面Env复合物的暴露导致抗体靶向作用，从而引发对病毒逃逸突变的选择。我们使用SIV/恒河猴模型来追踪有或没有针对Env抗体反应的动物在急性/早期感染期间Env变异的进化情况，发现在感染数周内有抗体反应的动物中存在显著变异。使用基于深度测序的适应性试验，我们发现与抗体逃逸相关的替换对固有复制能力几乎没有影响。能够轻易传播几乎不产生或不产生复制适应性代价的有利变化，可能是在持续免疫选择下维持持续复制的一种机制，使病毒能够在感染宿主中持续存在数月至数年。
