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长期、低水平的包膜 C2V3 刺激由高度多样化的病毒分离株引起,导致 HIV-1 感染个体中频繁出现广泛且强效的抗体中和作用。

Long-Term and Low-Level Envelope C2V3 Stimulation by Highly Diverse Virus Isolates Leads to Frequent Development of Broad and Elite Antibody Neutralization in HIV-1-Infected Individuals.

机构信息

Research Institute for Medicine, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.

Centro de Investigação Interdisciplinar Egas Moniz, Instituto Universitário Egas Moniz, Caparica, Portugal.

出版信息

Microbiol Spectr. 2022 Dec 21;10(6):e0163422. doi: 10.1128/spectrum.01634-22. Epub 2022 Nov 29.

Abstract

A minority of HIV-1-infected patients produce broadly neutralizing antibodies (bNAbs). Identification of viral and host correlates of bNAb production may help develop vaccines. We aimed to characterize the neutralizing response and viral and host-associated factors in Angola, which has one of the oldest, most dynamic, and most diverse HIV-1 epidemics in the world. Three hundred twenty-two HIV-1-infected adults from Angola were included in this retrospective study. Phylogenetic analysis of C2V3C3 gene sequences was used for virus subtyping. Env-binding antibody reactivity was tested against polypeptides comprising the C2, V3, and C3 regions. Neutralizing-antibody responses were determined against a reference panel of tier 2 Env pseudoviruses in TZM-bl cells; neutralizing epitope specificities were predicted using ClustVis. All subtypes were found, along with untypeable strains and recombinant forms. Notably, 56% of the patients developed cross neutralizing, broadly neutralizing, or elite neutralizing responses. Broad and elite neutralization was associated with longer infection time, subtype C, lower CD4 T cell counts, higher age, and higher titer of C2V3C3-specific antibodies relative to failure to develop bNAbs. Neutralizing antibodies targeted the V3-glycan supersite in most patients. V3 and C3 regions were significantly less variable in elite neutralizers than in weak neutralizers and nonneutralizers, suggesting an active role of V3C3-directed bNAbs in controlling HIV-1 replication and diversification. In conclusion, prolonged and low-level envelope V3C3 stimulation by highly diverse and ancestral HIV-1 isolates promotes the frequent elicitation of bNAbs. These results provide important clues for the development of an effective HIV-1 vaccine. Studies on neutralization by antibodies and their determinants in HIV-1-infected individuals have mostly been conducted in relatively recent epidemics caused by subtype B and C viruses. Results have suggested that elicitation of broadly neutralizing antibodies (bNAbs) is uncommon. The mechanisms underlying the elicitation of bNAbs are still largely unknown. We performed the first characterization of the plasma neutralizing response in a cohort of HIV-1-infected patients from Angola. Angola is characterized by an old and dynamic epidemic caused by highly diverse HIV-1 variants. Remarkably, more than half of the patients produced bNAbs, mostly targeting the V3-glycan supersite in HIV-1. This was associated with higher age, longer infection time, lower CD4 T cell counts, subtype C infection, or higher titer of C2V3C3-specific antibodies relative to patients that did not develop bNAbs. These results may help develop the next generation of vaccine candidates for HIV-1.

摘要

少数 HIV-1 感染者会产生广谱中和抗体(bNAb)。鉴定产生 bNAb 的病毒和宿主相关因素可能有助于开发疫苗。我们旨在描述安哥拉的中和反应以及病毒和宿主相关因素,因为安哥拉是世界上 HIV-1 流行时间最长、最活跃和最多样化的地区之一。这项回顾性研究纳入了 322 名来自安哥拉的 HIV-1 感染者。使用 C2V3C3 基因序列的系统发育分析对病毒进行亚型分型。用包含 C2、V3 和 C3 区域的多肽检测Env 结合抗体反应性。使用 TZM-bl 细胞对参考面板的 2 级 Env 假病毒进行中和抗体反应测定;使用 ClustVis 预测中和表位特异性。发现了所有亚型,以及无法分型的菌株和重组形式。值得注意的是,56%的患者产生了交叉中和、广谱中和或精英中和反应。广泛和精英中和与更长的感染时间、C 型、更低的 CD4 T 细胞计数、更高的年龄和更高的 C2V3C3 特异性抗体滴度相关,而未能产生 bNAb 则与之相反。中和抗体主要针对大多数患者的 V3-聚糖超位点。与弱中和和非中和者相比,精英中和者的 V3 和 C3 区域的变异性显著降低,这表明 V3C3 定向 bNAb 在控制 HIV-1 复制和多样化方面发挥了积极作用。总之,高度多样化和古老的 HIV-1 分离株对包膜 V3C3 的长期和低水平刺激促进了 bNAb 的频繁产生。这些结果为开发有效的 HIV-1 疫苗提供了重要线索。在 HIV-1 感染者中,对抗体及其决定因素的中和作用的研究主要集中在由 B 型和 C 型病毒引起的相对较新的流行中。结果表明,广谱中和抗体(bNAb)的产生并不常见。产生 bNAb 的机制在很大程度上仍不清楚。我们首次对来自安哥拉的 HIV-1 感染者队列中的血浆中和反应进行了表征。安哥拉的特点是由高度多样化的 HIV-1 变体引起的古老而活跃的流行。值得注意的是,超过一半的患者产生了 bNAb,主要针对 HIV-1 中的 V3-聚糖超位点。这与年龄较大、感染时间较长、CD4 T 细胞计数较低、C 型感染或 C2V3C3 特异性抗体滴度较高有关,而这些与未产生 bNAb 的患者相反。这些结果可能有助于开发下一代 HIV-1 疫苗候选物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9516/9769935/871fa297107d/spectrum.01634-22-f001.jpg

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