Department of Cell Biology, College of Life Science and Technology, Jinan Universitygrid.258164.c, Guangzhou, China.
Institute of Biomedicine, Jinan Universitygrid.258164.c, Guangzhou, China.
Microbiol Spectr. 2022 Dec 21;10(6):e0139322. doi: 10.1128/spectrum.01393-22. Epub 2022 Nov 7.
Human cytomegalovirus (HCMV) infects 36% to almost 100% of adults and causes severe complications only in immunocompromised individuals. HCMV viral surface trimeric (gH/gL/gO) and pentameric (gH/gL/UL128/UL130/UL131A) complexes play important roles in HCMV infection and tropism. Here, we isolated and identified a total of four neutralizing monoclonal antibodies (MAbs) derived from HCMV-seropositive blood donors. Based on their reactivity to HCMV trimer and pentamer, these MAbs can be divided into two groups. MAbs PC0012, PC0014, and PC0035 in group 1 bind both trimer and pentamer and neutralize CMV by interfering with the postattachment steps of CMV entering into cells. These three antibodies recognize antigenic epitopes clustered in a similar area, which are overlapped by the epitope recognized by the known neutralizing antibody MSL-109. MAb PC0034 in group 2 binds only to pentamer and neutralizes CMV by blocking the binding of pentamer to cells. Epitope mapping using pentamer mutants showed that amino acid T94 of the subunit UL128 and K27 of UL131A on the pentamer are key epitope-associated residues recognized by PC0034. This study provides new evidence and insight information on the importance of the development of the CMV pentamer as a CMV vaccine. In addition, these newly identified potent CMV MAbs can be attractive candidates for development as antibody therapeutics for the prevention and treatment of HCMV infection. The majority of the global population is infected with HCMV, but severe complications occur only in immunocompromised individuals. In addition, CMV infection is a major cause of birth defects in newborns. Currently, there are still no approved prophylactic vaccines or therapeutic monoclonal antibodies (MAbs) for clinical use against HCMV infection. This study identified and characterized a panel of four neutralizing MAbs targeting the HCMV pentamer complex with specific aims to identify a key protein(s) and antigenic epitopes in the HCMV pentamer complex. The study also explored the mechanism by which these newly identified antibodies neutralize HCMV in order to design better HCMV vaccines focusing on the pentamer and to provide attractive candidates for the development of effective cocktail therapeutics for the prevention and treatment of HCMV infection.
人类巨细胞病毒（HCMV）感染 36%至近 100%的成年人，仅在免疫功能低下的个体中引起严重并发症。HCMV 病毒表面三聚体（gH/gL/gO）和五聚体（gH/gL/UL128/UL130/UL131A）复合物在 HCMV 感染和嗜性中发挥重要作用。在这里，我们从 HCMV 血清阳性献血者中分离和鉴定了总共四种中和单克隆抗体（MAb）。根据它们对 HCMV 三聚体和五聚体的反应性，这些 MAb 可以分为两组。第 1 组的 MAb PC0012、PC0014 和 PC0035 结合三聚体和五聚体，并通过干扰 CMV 进入细胞的附着后步骤来中和 CMV。这三种抗体识别聚集在相似区域的抗原表位，这些表位与已知中和抗体 MSL-109 识别的表位重叠。第 2 组的 MAb PC0034 仅结合五聚体，并通过阻断五聚体与细胞的结合来中和 CMV。使用五聚体突变体进行表位作图表明，五聚体上的亚基 UL128 的氨基酸 T94 和 UL131A 的 K27 是 PC0034 识别的关键表位相关残基。这项研究提供了关于开发 CMV 五聚体作为 CMV 疫苗的重要性的新证据和见解信息。此外，这些新鉴定的强效 CMV MAb 可作为预防和治疗 HCMV 感染的抗体治疗候选物，具有吸引力。 全球大多数人都感染了 HCMV，但只有免疫功能低下的个体才会出现严重并发症。此外，CMV 感染是新生儿出生缺陷的主要原因。目前，尚无针对 HCMV 感染的预防性疫苗或治疗性单克隆抗体（MAb）获得批准用于临床。本研究鉴定并表征了一组针对 HCMV 五聚体复合物的四种中和 MAb，旨在鉴定 HCMV 五聚体复合物中的关键蛋白（多个）和抗原表位。该研究还探讨了这些新鉴定的抗体中和 HCMV 的机制，以便设计更好的针对五聚体的 HCMV 疫苗，并为预防和治疗 HCMV 感染提供有效的鸡尾酒治疗候选物。
