Human papillomavirus type 6 (HPV6) is the major etiologic agent of genital warts and recurrent respiratory papillomatosis. Although the commercial HPV vaccines cover HPV6, the neutralization sites and mode for HPV6 are poorly understood. Here, we identify the HPV6 neutralization sites and discriminate the inhibition of virus attachment and entry by three potent neutralizing antibodies (nAbs), 5D3, 17D5, and 15F7. Mutagenesis assays showed that these nAbs predominantly target surface loops BC, DE, and FG of HPV6 L1. Cryo-EM structures of the HPV6 pseudovirus (PsV) and its immune complexes revealed three distinct binding modalities - full-occupation-bound to capsid, top-center-bound-, and top-rim-bound to pentamers - and illustrated a structural atlas for three classes of antibody-bound footprints that are located at center-distal ring, center, and center-proximal ring of pentamer surface for 5D3, 17D5, and 15F7, respectively. Two modes of neutralization were identified: mAb 5D3 and 17D5 block HPV PsV from attaching to the extracellular matrix (ECM) and the cell surface, whereas 15F7 allows PsV attachment but prohibits PsV from entering the cell. These findings highlight three neutralization sites of HPV6 L1 and outline two antibody-mediated neutralization mechanisms against HPV6, which will be relevant for HPV virology and antiviral inhibitor design. HighlightsMajor neutralization sites of HPV6 were mapped on the pseudovirus cryo-EM structuremAb 15F7 binds HPV6 capsid with a novel top-rim binding modality and confers a post-attachment neutralizationmAb 17D5 binds capsid in top-centre manner but unexpectedly prevents virus from attachment to cell surface.

中文翻译：

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人乳头瘤病毒6的中和位点与病毒感染中的病毒附着和进入阶段有关。

6型人乳头瘤病毒（HPV6）是尖锐湿疣和反复呼吸道乳头状瘤病的主要病因。尽管商业HPV疫苗涵盖HPV6，但对HPV6的中和位点和方式知之甚少。在这里，我们确定了HPV6中和位点，并通过三种有效的中和抗体（nAbs），5D3、17D5和15F7区分了对病毒附着和进入的抑制作用。诱变分析表明，这些nAb主要靶向HPV6 L1的表面环BC，DE和FG。HPV6假病毒（PsV）的低温电磁结构及其免疫复合物揭示了三种不同的结合方式-全体结合到衣壳，顶部中心结合和五边体结合-并举例说明了结构图集位于中心-远端环，中心的三类抗体结合的印迹 和五聚体表面的中心近端环分别用于5D3、17D5和15F7。确定了两种中和模式：mAb 5D3和17D5阻止HPV PsV附着于细胞外基质（ECM）和细胞表面，而15F7允许PsV附着但禁止PsV进入细胞。这些发现突出了HPV6 L1的三个中和位点，并概述了针对HPV6的两个抗体介导的中和机制，这与HPV病毒学和抗病毒抑制剂的设计有关。亮点HPV6的主要中和位点被定位在假病毒cryo-EM结构上mAb 15F7以新颖的上边缘结合方式结合HPV6衣壳并赋予附着后中和mAb 17D5以最高中心的方式结合衣壳，但出乎意料地阻止了病毒附着到细胞表面。