Department of Medicine, Division of Infectious Diseases, University of California, Irvine School of Medicine, Irvine, California, USA.
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA.
J Virol. 2022 Jan 26;96(2):e0168921. doi: 10.1128/JVI.01689-21. Epub 2021 Nov 3.
The low abundance of envelope spikes and the inability of IgG to aggregate virions render HIV-1 an inadequate target for antibody-mediated clearance by phagocytes. In an attempt to improve the ability of antibody to mediate the internalization of HIV-1 virions, we generated multimers of the broadly neutralizing HIV-1-specific monoclonal antibody (MAb) VRC01 using site-directed mutagenesis of the Fc segment. We then measured virion internalization using primary human monocytes and neutrophils. We found that, in the absence of complement, immune complexes consisting of HIV-1 virions and VRC01 multimers were slightly more efficiently internalized than were complexes formed with monomeric VRC01. The presence of complement, however, greatly augmented internalization of immune complexes formed with the multimeric MAb but had little impact on monomeric MAb-mediated internalization. Multimerization and the presence of complement overcome the limited ability of monomeric antibody to mediate internalization of HIV-1 virions and may thus provide a therapeutic approach to clearing virus. Antibody-mediated internalization of HIV-1 by phagocytes, a potential mechanism for clearing virus, is very inefficient. In an effort to improve viral clearance, we produced a multimeric form of the broadly neutralizing monoclonal antibody VRC01. We found that VRC01 antibody multimers (primarily hexamers) were only slightly more efficient in mediating HIV-1 internalization than was monomeric VRC01. However, the addition of complement resulted in substantially greater internalization of multimer-opsonized virus. In contrast, complement had little if any impact on internalization of monomer-opsonized virus. Therefore, antibody multimerization in combination with complement may overcome the limited ability of monomeric antibody to mediate internalization of HIV-1 virions. Our findings may provide a therapeutic approach to clearing virus.
包膜刺突的低丰度和 IgG 不能聚集病毒颗粒，使得 HIV-1 成为吞噬细胞通过抗体介导清除的不足靶标。为了提高抗体介导 HIV-1 病毒颗粒内化的能力，我们使用 Fc 片段的定点突变生成了广泛中和的 HIV-1 特异性单克隆抗体（MAb）VRC01 的多聚体。然后，我们使用原代人单核细胞和中性粒细胞测量病毒颗粒的内化。我们发现，在没有补体的情况下，由 HIV-1 病毒颗粒和 VRC01 多聚体组成的免疫复合物比由单体 VRC01 形成的复合物稍微更有效地被内化。然而，补体的存在大大增强了与多聚体 MAb 形成的免疫复合物的内化，但对单体 MAb 介导的内化几乎没有影响。多聚化和补体的存在克服了单体抗体介导 HIV-1 病毒颗粒内化的能力有限，因此可能为清除病毒提供一种治疗方法。吞噬细胞介导的 HIV-1 内化是清除病毒的一种潜在机制，但效率非常低。为了提高病毒清除效率，我们制备了广泛中和的单克隆抗体 VRC01 的多聚体形式。我们发现 VRC01 抗体多聚体（主要是六聚体）介导 HIV-1 内化的效率仅略高于单体 VRC01。然而，补体的加入导致多聚体包被的病毒的内化大大增加。相比之下，补体对单体包被的病毒的内化几乎没有影响。因此，抗体多聚化与补体结合可能克服单体抗体介导 HIV-1 病毒颗粒内化的能力有限。我们的研究结果可能为清除病毒提供一种治疗方法。
