Institute of Infectious Diseases and Molecular Medicine, Division of Medical Virology, Department of Pathology, University of Cape Towngrid.7836.a, Cape Town, South Africa.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
J Virol. 2022 Jul 27;96(14):e0032422. doi: 10.1128/jvi.00324-22. Epub 2022 Jun 27.
Induction of broadly neutralizing antibodies (bNAbs) to HIV and other diverse pathogens will likely require the use of multiple immunogens. An understanding of the dynamics of antibody development to multiple diverse but related antigens would facilitate the rational design of immunization strategies. Here, we characterize, in detail, the development of neutralizing antibodies in three individuals coinfected with several divergent HIV variants. Two of these coinfected individuals developed additive or cross-neutralizing antibody responses. However, interference was observed in the third case, with neutralizing antibody responses to one viral variant arising to the near exclusion of neutralizing responses to the other. Longitudinal characterization of the diversity in the Envelope glycoprotein trimer (Env) structure showed that in the individual who developed the broadest neutralizing antibodies, circulating viruses shared a conserved epitope on the trimer apex that was targeted by cross-neutralizing antibodies. In contrast, in the other two individuals, diversity was distributed across Env. Taken together, these data highlight that multiple related immunogens can result in immune interference. However, they also suggest that immunogen cocktails presenting shared, conserved neutralizing epitopes in a variable background may focus broadly neutralizing antibody responses to these targets. Despite being the focus of extensive research, we still do not know how to reproducibly elicit cross-neutralizing antibodies against variable pathogens by vaccination. Here, we characterize the antibody responses in people coinfected with more than one HIV variant, providing insights into how the use of antigen "cocktails" might affect the breadth of the elicited neutralizing antibody response and how the relatedness of the antigens may shape this.
诱导针对 HIV 和其他多种病原体的广谱中和抗体（bNAbs）可能需要使用多种免疫原。了解针对多种不同但相关抗原的抗体产生动力学将有助于合理设计免疫策略。在这里，我们详细描述了三名同时感染多种不同 HIV 变体的个体中中和抗体的发展情况。这两名同时感染的个体产生了相加或交叉中和抗体反应。然而，在第三种情况下观察到了干扰，对一种病毒变体的中和抗体反应几乎排除了对另一种病毒变体的中和抗体反应。对 Envelope 糖蛋白三聚体（Env）结构多样性的纵向特征分析表明，在产生最广泛中和抗体的个体中，循环病毒共享三聚体顶端的保守表位，该表位被交叉中和抗体靶向。相比之下，在另外两个人中，多样性分布在 Env 上。综上所述，这些数据表明，多种相关免疫原可能导致免疫干扰。然而，它们也表明，呈递共享、保守中和表位的免疫原鸡尾酒在可变背景下可能会将广泛中和抗体反应集中在这些靶标上。尽管是广泛研究的焦点，但我们仍然不知道如何通过接种疫苗来重复地诱导针对可变病原体的交叉中和抗体。在这里，我们描述了同时感染多种 HIV 变体的人的抗体反应，深入了解了使用抗原“鸡尾酒”如何影响所引起的中和抗体反应的广度，以及抗原的相关性如何塑造这种反应。
