Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA.
School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
Viruses. 2022 Jul 9;14(7):1508. doi: 10.3390/v14071508.
Human cytomegalovirus (CMV) utilizes different glycoproteins to enter into fibroblast and epithelial cells. A trimer of glycoproteins H, L, and O (gH/gL/gO) is required for entry into all cells, whereas a pentamer of gH/gL/UL128/UL130/UL131A is selectively required for infection of epithelial, endothelial, and some myeloid-lineage cells, but not of fibroblasts. Both complexes are of considerable interest for vaccine and immunotherapeutic development but present a conundrum: gH/gL-specific antibodies have moderate potency yet neutralize CMV entry into all cell types, whereas pentamer-specific antibodies are more potent but do not block fibroblast infection. Which cell types and neutralizing activities are important for protective efficacy remain unclear. Here, we present evidence that certain CMV strains have evolved polymorphisms in gO to evade trimer-specific neutralizing antibodies. Using luciferase-tagged variants of strain TB40/E in which the native gO is replaced by gOs from other strains, we tested the effects of gO polymorphisms on neutralization by monoclonal antibodies (mAbs) targeting four independent epitopes in gH/gL that are common to both trimer and pentamer. Neutralization of fibroblast entry by three mAbs displayed a range of potencies that depended on the gO type, a fourth mAb failed to neutralize fibroblast entry regardless of the gO type, while neutralization of epithelial cell entry by all four mAbs was potent and independent of the gO type. Thus, specific polymorphisms in gO protect the virus from mAb neutralization in the context of fibroblast but not epithelial cell entry. No influence of gO type was observed for protection against CMV hyperimmune globulin or CMV-seropositive human sera, suggesting that antibodies targeting protected gH/gL epitopes represent a minority of the polyclonal neutralizing repertoire induced by natural infection.
人类巨细胞病毒 (CMV) 利用不同的糖蛋白进入成纤维细胞和上皮细胞。糖蛋白 H、L 和 O（gH/gL/gO）三聚体是进入所有细胞所必需的，而 gH/gL/UL128/UL130/UL131A 五聚体则选择性地需要感染上皮细胞、内皮细胞和一些髓系细胞，但不需要感染成纤维细胞。这两种复合物都对疫苗和免疫治疗的发展具有重要意义，但存在一个难题：gH/gL 特异性抗体具有中等效力，但能中和 CMV 进入所有细胞类型的能力，而五聚体特异性抗体更有效力，但不能阻止成纤维细胞感染。哪些细胞类型和中和活性对保护效力重要仍不清楚。在这里，我们提供的证据表明，某些 CMV 株已经进化出 gO 中的多态性，以逃避三聚体特异性中和抗体。我们使用荧光素酶标记的 TB40/E 株变体，其中天然 gO 被来自其他株的 gOs 取代，我们测试了 gO 多态性对靶向 gH/gL 中四个独立表位的单克隆抗体 (mAb) 中和的影响，这些表位在三聚体和五聚体中都是共同的。三种 mAb 对成纤维细胞进入的中和显示出一系列效力范围，这取决于 gO 类型，第四种 mAb 无论 gO 类型如何都未能中和成纤维细胞进入，而所有四种 mAb 对上皮细胞进入的中和都是有效的，并且与 gO 类型无关。因此，gO 中的特定多态性在成纤维细胞但不在上皮细胞进入的情况下保护病毒免受 mAb 中和。gO 类型对 CMV 高免疫球蛋白或 CMV 血清阳性的人血清的保护没有影响，这表明针对受保护的 gH/gL 表位的抗体代表了由自然感染诱导的多克隆中和 repertoire 的少数。
