Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk
Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk
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DOI：
10.1172/jci126391
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发表时间：
2019-11-01
影响因子：
15.9
通讯作者：
Novak, Richard
中科院分区：
文献类型：
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作者：
Neidich, Scott D.;Fong, Youyi;Novak, Richard
HVTN 505是一项预防性疫苗有效性试验，在美国包皮环切术、ads血清阴性的男性和变性男性中检测DNA和重组腺病毒血清5型（rAd5）。已确定的降低HIV-1风险的免疫相关因素和病毒筛分析表明，尽管缺乏总体效力，但疫苗引发的反应对感染HIV-1病毒施加了压力。为了探究抗体与HIV-1风险相关的机制，我们检测了Fc γ受体（Fc γ Rs）的抗原特异性抗体募集、抗体依赖性细胞吞噬（ADCP）和抗包膜（anti-Env） IgG3的作用。在预先指定的免疫相关性分析中，抗体依赖的单核细胞吞噬和与Fc γ RIIa结合的抗体与降低HIV-1风险相关。随访分析显示，抗env IgG3宽度与降低HIV-1风险相关，抗env IgA通过Fc效应功能负修饰感染风险，当ADCP、Env-Fc γ RIIa和IgG3结合高时，具有特定Fc γ RIIa单核苷酸多态性位点的疫苗接种者与降低HIV-1风险相关性更强。此外，在获得HIV-1的疫苗接种者中，Fc γ RIIa参与与病毒载量设定值降低相关。这些数据支持疫苗诱导的抗HIV-1 Env IgG3、fcr抗体结合和吞噬作用作为HIV-1预防的潜在机制。
HVTN 505 is a preventative vaccine efficacy trial testing DNA followed by recombinant adenovirus serotype 5 (rAd5) in circumcised, Ads-seronegative men and transgendered persons who have sex with men in the United States. Identified immune correlates of lower HIV-1 risk and a virus sieve analysis revealed that, despite lacking overall efficacy, vaccine-elicited responses exerted pressure on infecting HIV-1 viruses. To interrogate the mechanism of the antibody correlate of HIV-1 risk, we examined antigen-specific antibody recruitment of Fc gamma receptors (Fc gamma Rs), antibody-dependent cellular phagocytosis (ADCP), and the role of anti-envelope (anti-Env) IgG3. In a prespecified immune correlates analysis, antibody-dependent monocyte phagocytosis and antibody binding to Fc gamma RIIa correlated with decreased HIV-1 risk. Follow-up analyses revealed that anti-Env IgG3 breadth correlated with reduced HIV-1 risk, anti-Env IgA negatively modified infection risk by Fc effector functions, and that vaccine recipients with a specific Fc gamma RIIa single-nucleotide polymorphism locus had a stronger correlation with decreased HIV-1 risk when ADCP, Env-Fc gamma RIIa, and IgG3 binding were high. Additionally, Fc gamma RIIa engagement correlated with decreased viral load setpoint in vaccine recipients who acquired HIV-1. These data support a role for vaccine-elicited anti-HIV-1 Env IgG3, antibody engagement of FcRs, and phagocytosis as potential mechanisms for HIV-1 prevention.