Convergent HIV evolution across species Human immunodeficiency virus (HIV) has a highly diverse envelope protein that it uses to target human cells, and the complexity of the viral envelope has stymied vaccine development. Roark et al. report that the immediate and short-term evolutionary potential of the HIV envelope is constrained because of a number of essential functions, including antibody escape. Consequently, when introduced into humans as HIV or into rhesus macaque monkeys as chimeric simian-human immunodeficiency virus, homologous envelope glycoproteins appear to exhibit conserved patterns of sequence evolution, in some cases eliciting broadly neutralizing antibodies in both hosts. Conserved patterns of envelope variation and homologous B cell responses in humans and monkeys represent examples of convergent evolution that may serve to guide HIV vaccine development. Science, this issue p. eabd2638 HIV antibody coevolution in rhesus macaques mirrors similar processes in the development of human broadly neutralizing anti-HIV antibodies. INTRODUCTION It is widely believed that the development of an effective neutralizing antibody–based HIV-1 vaccine will require consistent activation of multiple germline precursor B cells that express immunoglobulin receptors specific for one or more of the canonical broadly neutralizing antibody (bNAb) epitope clusters, followed by efficient antigen-driven selection for antibody affinity maturation. How to accomplish this feat by immunization has proven to be a daunting scientific challenge. One roadblock to rational HIV-1 vaccine design is the lack of a suitable outbred primate model in which bNAbs can be commonly induced, thereby enabling the molecular, biological, and immunological mechanisms responsible for such responses to be studied in a reproducible and iterative fashion. RATIONALE Given that most HIV-1 bNAbs identified to date have come from humans chronically infected by HIV-1, we hypothesized that one means to elicit such antibodies in primates might be by infecting rhesus macaques (RMs) with simian-human immunodeficiency virus (SHIV) strains that bear primary HIV-1 envelope proteins (Envs), including those that induced bNAbs in humans. SHIV-infected RMs could then be used to assess the potential of particular HIV-1 Envs to elicit bNAbs and to characterize the coevolutionary pathways of bNAb lineages and the cognate Env intermediates that elicited them, thus serving as a molecular guide for rational vaccine design. Recent innovations in SHIV design make this experimental strategy testable. RESULTS Neutralizing antibodies elicited by HIV-1 in naturally infected humans coevolve with viral Envs in distinctive molecular patterns, in some cases acquiring substantial breadth. We constructed SHIVs bearing primary transmitted/founder Envs from three HIV–1 infected humans who developed bNAbs and used these SHIVs to infect 22 RMs. Seven monkeys developed bNAbs that exhibited a wide range of breadth and potency. Unexpectedly, SHIV infections elicited molecular patterns of Env-antibody coevolution in monkeys that mirrored what was seen in humans infected by HIV-1 strains bearing homologous Envs. Similarities included conserved immunogenetic, structural, and chemical solutions to epitope recognition and precise Env–amino acid substitutions, insertions, and deletions leading to virus persistence. One rhesus antibody, capable of neutralizing 49% of a 208-strain global virus panel, contained a 24–amino acid heavy chain complementarity-determining region 3 (HCDR3) with a sulfated tyrosine at its tip; this rhesus bNAb exhibited a V2 apex mode of recognition similar to human bNAbs PGT145 and PCT64-35S, with critical interactions involving lysine or arginine residues at Env positions 121, 166, and 169 and an N-linked glycan at position 160. Another rhesus antibody bound the CD4 binding site by CD4 mimicry mirroring human bNAbs 8ANC131, CH235, and VRC01. In other SHIV-infected animals, bNAb responses targeted a canonical V3 high mannose patch epitope cluster that included Env residues 324GDIR327 and N332. Molecular patterns of epitope evolution enabling virus escape, and at the same time promoting bNAb affinity maturation, were similar in SHIV-infected RMs and HIV-1–infected humans. CONCLUSION SHIV infection of RMs is the only model system other than naturally infected humans where the immunogen (Env) coevolves with neutralizing antibodies. The high mutability and dynamic replication of HIV-1 and SHIV in vivo result in a constantly evolving virus quasispecies, which means that Envs with binding affinities sufficient to drive bNAb lineage affinity maturation are continuously being generated. SHIV-infected macaques may thus provide insights for vaccine design by enabling the identification of Env intermediates that can guide the evolution of precursor B cells through stages of affinity maturation leading to breadth and potency. Envelope-antibody coevolution in monkey and human. Env-antibody coevolution in SHIV-infected rhesus macaques mirrors that in HIV-1–infected humans, including the elicitation of broadly neutralizing antibodies. The illustration depicts a mirror with images, left to right, of organism, longitudinal changes in viral Env sequence, Env trimer recognition by virus-elicited broadly neutralizing antibodies, and atomic-level details of paratope–epitope interactions. IMAGE: J. GORMAN, NIH Neutralizing antibodies elicited by HIV-1 coevolve with viral envelope proteins (Env) in distinctive patterns, in some cases acquiring substantial breadth. We report that primary HIV-1 envelope proteins—when expressed by simian-human immunodeficiency viruses in rhesus macaques—elicited patterns of Env-antibody coevolution very similar to those in humans, including conserved immunogenetic, structural, and chemical solutions to epitope recognition and precise Env–amino acid substitutions, insertions, and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2 apex mode of recognition like that of human broadly neutralizing antibodies (bNAbs) PGT145 and PCT64-35S. Another rhesus antibody bound the CD4 binding site by CD4 mimicry, mirroring human bNAbs 8ANC131, CH235, and VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design.

中文翻译：

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猕猴中 HIV-1 Env-抗体协同进化导致中和广度的概括


HIV 跨物种进化趋同人类免疫缺陷病毒 (HIV) 具有高度多样化的包膜蛋白，可用于靶向人类细胞，而病毒包膜的复杂性阻碍了疫苗的开发。罗克等人。报告称，由于许多基本功能（包括抗体逃逸），HIV 包膜的直接和短期进化潜力受到限制。因此，当作为HIV引入人类或作为嵌合猿-人类免疫缺陷病毒引入恒河猴时，同源包膜糖蛋白似乎表现出保守的序列进化模式，在某些情况下在两种宿主中引发广泛中和抗体。人类和猴子中包膜变异和同源 B 细胞反应的保守模式代表了趋同进化的例子，可能有助于指导 HIV 疫苗的开发。科学，本期第 14 页。恒河猴中的 eabd2638 HIV 抗体共同进化反映了人类广泛中和抗 HIV 抗体发展的类似过程。引言 人们普遍认为，开发一种有效的基于中和抗体的 HIV-1 疫苗需要持续激活多个种系前体 B 细胞，这些细胞表达对一个或多个典型广泛中和抗体 (bNAb) 表位簇具有特异性的免疫球蛋白受体，其次是有效的抗原驱动选择以实现抗体亲和力成熟。事实证明，如何通过免疫来完成这一壮举是一项艰巨的科学挑战。 合理设计 HIV-1 疫苗的一个障碍是缺乏合适的近交灵长类动物模型，在该模型中 bNAb 可以被普遍诱导，从而能够以可重复和迭代的方式研究负责此类反应的分子、生物和免疫机制。鉴于迄今为止发现的大多数 HIV-1 bNAb 来自长期感染 HIV-1 的人类，我们假设在灵长类动物中引发此类抗体的一种方法可能是用猿猴人类免疫缺陷病毒 (SHIV) 感染恒河猴 (RM) ）带有初级 HIV-1 包膜蛋白 (Envs) 的菌株，包括那些在人类中诱导 bNAb 的菌株。然后，感染 SHIV 的 RM 可用于评估特定 HIV-1 Env 引发 bNAb 的潜力，并表征 bNAb 谱系和引发它们的同源 Env 中间体的共同进化途径，从而作为合理疫苗设计的分子指南。 SHIV 设计的最新创新使这一实验策略具有可测试性。结果自然感染人类中 HIV-1 引发的中和抗体与病毒包膜以独特的分子模式共同进化，在某些情况下获得了相当大的广度。我们从三名 HIV-1 感染者中构建了携带原发性/创建者 Env 的 SHIV，这些感染者开发了 bNAb，并使用这些 SHIV 感染了 22 个 RM。七只猴子开发出了具有广泛广度和效力的 bNAb。出乎意料的是，SHIV 感染在猴子中引发了 Env 抗体协同进化的分子模式，这与感染带有同源 Env 的 HIV-1 毒株的人类中所见的情况相似。 相似之处包括表位识别的保守免疫遗传学、结构和化学解决方案以及导致病毒持久存在的精确的包膜氨基酸取代、插入和删除。一种恒河猴抗体能够中和 208 株全球病毒组中 49% 的病毒，含有 24 个氨基酸的重链互补决定区 3 (HCDR3)，其尖端有一个硫酸化酪氨酸；该恒河猴 bNAb 表现出与人 bNAb PGT145 和 PCT64-35S 类似的 V2 顶端识别模式，关键相互作用涉及 Env 位点 121、166 和 169 的赖氨酸或精氨酸残基以及位点 160 的 N 连接聚糖。 另一种恒河猴抗体通过镜像人 bNAb 8ANC131、CH235 和 VRC01 的 CD4 拟态结合 CD4 结合位点。在其他感染 SHIV 的动物中，bNAb 反应针对典型的 V3 高甘露糖斑块表位簇，其中包括 Env 残基 324GDIR327 和 N332。在 SHIV 感染的 RM 和 HIV-1 感染的人类中，使病毒逃逸并同时促进 bNAb 亲和力成熟的表位进化的分子模式是相似的。结论 RMs 的 SHIV 感染是除了自然感染的人类之外唯一的免疫原 (Env) 与中和抗体共同进化的模型系统。 HIV-1和SHIV在体内的高突变性和动态复制导致病毒准种不断进化，这意味着具有足以驱动bNAb谱系亲和力成熟的结合亲和力的Env不断产生。因此，感染 SHIV 的猕猴可以通过识别 Env 中间体来为疫苗设计提供见解，这些中间体可以指导前体 B 细胞通过亲和力成熟阶段的进化，从而获得广度和效力。 猴子和人类的包膜抗体共同进化。感染 SHIV 的恒河猴中的环境抗体协同进化与感染 HIV-1 的人类相似，包括引发广泛中和抗体。该插图描绘了一面镜子，从左到右显示生物体的图像、病毒 Env 序列的纵向变化、病毒引发的广泛中和抗体对 Env 三聚体的识别，以及互补位-表位相互作用的原子级细节。图片：J. GORMAN，NIH HIV-1 引发的中和抗体与病毒包膜蛋白 (Env) 以独特的模式共同进化，在某些情况下获得相当大的广度。我们报告说，初级 HIV-1 包膜蛋白（当在恒河猴中由猿猴-人类免疫缺陷病毒表达时）引发了与人类非常相似的 Env-抗体协同进化模式，包括保守的免疫遗传学、结构和化学解决方案，以进行表位识别和精确预测。 Env——导致病毒持久存在的氨基酸取代、插入和缺失。一种恒河猴抗体能够中和 208 株组中 49% 的抗体，其结构揭示了 V2 顶端识别模式，类似于人类广泛中和抗体 (bNAb) PGT145 和 PCT64-35S。另一种恒河猴抗体通过 CD4 拟态结合 CD4 结合位点，镜像人 bNAb 8ANC131、CH235 和 VRC01。因此，猕猴中的病毒-抗体协同进化可以概括人类 bNAb 的发育特征，从而指导 HIV-1 免疫原的设计。