Broadly Neutralizing Antibodies Display Potential for Prevention of HIV-1 Infection of Mucosal Tissue Superior to That of Nonneutralizing Antibodies.
Broadly Neutralizing Antibodies Display Potential for Prevention of HIV-1 Infection of Mucosal Tissue Superior to That of Nonneutralizing Antibodies.
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DOI：
10.1128/jvi.01762-16
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发表时间：
2017-01-01
影响因子：
5.4
通讯作者：
Shattock RJ
中科院分区：
文献类型：
--
作者：
Cheeseman HM;Olejniczak NJ;Rogers PM;Evans AB;King DFL;Ziprin P;Liao HX;Haynes BF;Shattock RJ
定义的关键参数介导的有效抗体阻断HIV-1的收购粘膜组织内可能证明是至关重要的有效的疫苗开发和预防性使用的单克隆抗体。虽然直接抗体介导的中和对无细胞病毒非常有效，但靶向包膜脆弱性不同位点的抗体可能显示出对粘膜感染的不同活性。非中和抗体（nnAb）也可能通过Fc γ受体（FcγR）介导的抑制作用影响粘膜传播事件。在这项研究中，对一组广泛中和抗体（bnAbs）和nnAbs（包括与RV 144疫苗试验中的保护相关的抗体）进行了筛选，以确定其在一系列细胞和粘膜组织模型中阻断HIV-1获得和复制的能力。通过TZM-bl感染测定确定的中和效力不能完全预测粘膜组织中的活性。在所有细胞和组织模型中，CD 4结合位点（CD 4 bs）特异性bnAb，特别是VRC 01，在阻断HIV-1感染方面是一致的。近膜外部区域（MPER）（2F 5）和外部结构域聚糖（2G 12）bnAbs也有效预防粘膜组织感染，而靶向V1-V2聚糖（PG 9和PG 16）的bnAbs的保护功效差异更大。相比之下，nnAb单独和组合，虽然在一系列细胞测定中有活性，但对粘膜组织的HIV-1感染的保护性较差。这些数据表明，组织驻留效应细胞数量和低FcγR表达可能限制了nnAb预防初始感染灶建立的潜力。由特异性bnAb提供的固体保护清楚地证明了它们在预防感染的粘膜入口处的HIV-1感染方面优于非中和抗体的上级潜力。 重要性介导有效抗体阻断粘膜组织内HIV-1获得的关键参数尚未确定。虽然bnAb对无细胞病毒非常有效，但它们不会被当前的候选疫苗诱导。然而，疫苗容易诱导的nnAb可通过其Fc-γ受体的接合触发抗体依赖性细胞效应子功能。在RV 144疫苗效力试验中，Fc介导的抗病毒活性被认为是降低HIV-1风险的次要相关因素，表明保护可能在缺乏经典中和的情况下介导。为了帮助疫苗设计和选择用于被动保护策略的抗体，我们评估了一系列bnAb和nnAb阻断粘膜组织离体攻击的潜力。我们的数据清楚地表明中和抗体在预防粘膜获得性感染方面具有上级功效。这些结果强调了保持HIV-1疫苗研究的中心焦点在诱导有效中和抗体上的重要性。
Definition of the key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue may prove critical to effective vaccine development and the prophylactic use of monoclonal antibodies. Although direct antibody-mediated neutralization is highly effective against cell-free virus, antibodies targeting different sites of envelope vulnerability may display differential activity against mucosal infection. Nonneutralizing antibodies (nnAbs) may also impact mucosal transmission events through Fc-gamma receptor (FcγR)-mediated inhibition. In this study, a panel of broadly neutralizing antibodies (bnAbs) and nnAbs, including those associated with protection in the RV144 vaccine trial, were screened for the ability to block HIV-1 acquisition and replication across a range of cellular and mucosal tissue models. Neutralization potency, as determined by the TZM-bl infection assay, did not fully predict activity in mucosal tissue. CD4-binding site (CD4bs)-specific bnAbs, in particular VRC01, were consistent in blocking HIV-1 infection across all cellular and tissue models. Membrane-proximal external region (MPER) (2F5) and outer domain glycan (2G12) bnAbs were also efficient in preventing infection of mucosal tissues, while the protective efficacy of bnAbs targeting V1-V2 glycans (PG9 and PG16) was more variable. In contrast, nnAbs alone and in combinations, while active in a range of cellular assays, were poorly protective against HIV-1 infection of mucosal tissues. These data suggest that tissue resident effector cell numbers and low FcγR expression may limit the potential of nnAbs to prevent establishment of the initial foci of infection. The solid protection provided by specific bnAbs clearly demonstrates their superior potential over that of nonneutralizing antibodies for preventing HIV-1 infection at the mucosal portals of infection. IMPORTANCE Key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue have not been defined. While bnAbs are highly effective against cell-free virus, they are not induced by current vaccine candidates. However, nnAbs, readily induced by vaccines, can trigger antibody-dependent cellular effector functions, through engagement of their Fc-gamma receptors. Fc-mediated antiviral activity has been implicated as a secondary correlate of decreased HIV-1 risk in the RV144 vaccine efficacy trial, suggesting that protection might be mediated in the absence of classical neutralization. To aid vaccine design and selection of antibodies for use in passive protection strategies, we assessed a range of bnAbs and nnAbs for their potential to block ex vivo challenge of mucosal tissues. Our data clearly indicate the superior efficacy of neutralizing antibodies in preventing mucosal acquisition of infection. These results underscore the importance of maintaining the central focus of HIV-1 vaccine research on the induction of potently neutralizing antibodies.