Lynch Lab, Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States.
Jones Lab, Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, United States.
Front Immunol. 2021 Sep 15;12:710327. doi: 10.3389/fimmu.2021.710327. eCollection 2021.
Although antiretroviral therapy (ART) successfully suppresses HIV-1 replication, ART-treated individuals must maintain therapy to avoid rebound from an integrated viral reservoir. Strategies to limit or clear this reservoir are urgently needed. Individuals infected for longer periods prior to ART appear to harbor more genetically diverse virus, but the roles of duration of infection and viral diversity in the humoral immune response remain to be studied. We aim to clarify a role, if any, for autologous and heterologous antibodies in multi-pronged approaches to clearing infection. To that end, we have characterized the breadths and potencies of antibody responses in individuals with varying durations of infection and HIV-1 envelope ( gene diversity as well as the sensitivity of their inducible virus reservoir to broadly neutralizing antibodies (bNAbs). Plasma was collected from 8 well-characterized HIV-1 males on ART with varied durations of active infection. HIV from reservoir-derived outgrowth viruses were amplified and single genome sequenced in order to measure genetic diversity in each participant. IgG from plasma was analyzed for binding titers against gp41 and gp120 proteins, and for neutralizing titers against a global HIV-1 reference panel as well as autologous outgrowth viruses. The sensitivity to bNAbs of these same autologous viruses was measured. Overall, we observed that greater diversity was associated with higher neutralizing titers against the global panel and also increased resistance to certain bNAbs. Despite the presence of robust anti-HIV-1 antibody titers, we did not observe potent neutralization against autologous viruses. In fact, 3 of 8 participants harbored viruses that were completely resistant to the highest tested concentration of autologous IgG. That this lack of neutralization was observed regardless of ART duration or viral diversity suggests that the inducible reservoir harbors 'escaped' viruses (that co-evolved with autologous antibody responses), rather than proviruses archived from earlier in infection. Finally, we observed that viruses resistant to autologous neutralization remained sensitive to bNAbs, especially CD4bs and MPER bNAbs. Overall, our data suggest that the inducible reservoir is relatively resistant to autologous antibodies and that individuals with limited virus variation in the gene, such as those who start ART early in infection, are more likely to be sensitive to bNAb treatment.
尽管抗逆转录病毒疗法（ART）成功地抑制了 HIV-1 的复制，但接受 ART 治疗的个体必须维持治疗，以避免整合的病毒库出现反弹。目前迫切需要限制或清除这种病毒库的策略。在接受 ART 治疗之前感染时间较长的个体似乎携带更多遗传多样化的病毒，但感染时间和病毒多样性在体液免疫反应中的作用仍有待研究。我们旨在阐明在清除感染的多管齐下方法中，自体和异源抗体是否有作用。为此，我们已经描述了具有不同感染时间和 HIV-1 包膜（基因多样性的个体中抗体反应的广度和效力，以及他们诱导的病毒库对广泛中和抗体（bNAbs）的敏感性。从 8 名接受 ART 治疗的特征明确的 HIV-1 男性个体中采集血浆，他们的感染时间不同。为了测量每个参与者的遗传多样性，从储库衍生的外生病毒中扩增并对单基因组进行测序。分析血浆中的 IgG 针对 gp41 和 gp120 蛋白的结合滴度，以及针对全球 HIV-1 参考面板以及自体外生病毒的中和滴度。还测量了这些相同的自体病毒对 bNAbs 的敏感性。总体而言，我们观察到更大的多样性与针对全球面板的更高中和滴度以及对某些 bNAbs 的更高抗性相关。尽管存在强大的抗 HIV-1 抗体滴度，但我们没有观察到针对自体病毒的有效中和作用。事实上，8 名参与者中有 3 名个体的病毒对测试浓度最高的自体 IgG 完全具有抗性。无论 ART 持续时间或病毒多样性如何，都观察到这种缺乏中和作用表明可诱导的储库中存在“逃逸”病毒（与自体抗体反应共同进化），而不是来自感染早期的前病毒。最后，我们观察到对自体中和作用具有抗性的病毒仍然对 bNAbs敏感，特别是对 CD4bs 和 MPER bNAbs 敏感。总体而言，我们的数据表明，可诱导的储库对自体抗体相对具有抗性，并且在基因中病毒变异有限的个体，例如那些在感染早期开始接受 ART 的个体，更有可能对 bNAb 治疗敏感。
