Wang Hsuan-Yuan, Taher Husam, Kreklywich Craig N, Schmidt Kimberli A, Scheef Elizabeth A, Barfield Richard, Otero Claire E, Valencia Sarah M, Zhang Ke, Callahan Claire, Monticolo Francesco, Qiao Yueqing, Gilbride Roxanne M, Crooks Chelsea M, Mirza Anne, Knight Kelsey, Moström Matilda J, Manuel Tabitha D, Sprehe Lesli, Kendall Savannah, Burgt Nathan Vande, Kowalik Timothy F, Barry Peter A, Hansen Scott G, Shu Jian, Tarantal Alice F, Chan Cliburn, Streblow Daniel N, Picker Louis J, Kaur Amitinder, Früh Klaus, Permar Sallie R, Malouli Daniel
Department of Pediatrics, Weill Cornell Medicine, New York, NY 10065, USA.
Duke University Medical Center, Durham, NC 27710, USA.
Sci Transl Med. 2025 Mar 12;17(789):eadm8961. doi: 10.1126/scitranslmed.adm8961.
Congenital cytomegalovirus (cCMV) is the leading infectious cause of neonatal neurological impairment worldwide, but the viral factors enabling vertical spread across the placenta remain undetermined. The pentameric complex (PC), composed of the subunits gH/gL/UL128/UL130/UL131A, has been demonstrated to be important for entry into nonfibroblast cells in vitro. These findings link the PC to broad cell tropism and virus dissemination in vivo, denoting all subunits as potential targets for intervention strategies and vaccine development. To determine the relevance of the PC for congenital transmission in a translational nonhuman primate model, we engineered a rhesus CMV (RhCMV) mutant lacking the orthologs of UL128 and UL130, which demonstrated diminished infection of epithelial cells in vitro. However, intravenous inoculation of either CD4 T cell-depleted or immunocompetent RhCMV-seronegative pregnant rhesus macaques (RMs) in the early second trimester with the PC-deficient mutant resulted in maternal RhCMV peak plasma viremia similar to inoculations with PC-intact RhCMV, although virus shedding in saliva and urine was limited. Infections with the PC-intact virus induced IgG responses that neutralized RhCMV entry into epithelial cells in tissue culture. These responses were reduced, but not absent, from animals infected with the PC-deficient virus, which also induced IgG responses against gH. Moreover, congenital CMV transmission was confirmed in multiple animals infected with PC-deficient virus by detecting viral DNA in the amniotic fluid, indicating that transplacental transmission in RMs is not contingent on the PC.
先天性巨细胞病毒（cCMV）是全球新生儿神经功能障碍的主要感染原因，但促使病毒垂直穿过胎盘传播的病毒因素仍未明确。由gH/gL/UL128/UL130/UL131A亚基组成的五聚体复合物（PC）已被证明在体外进入非成纤维细胞过程中起重要作用。这些发现将PC与体内广泛的细胞嗜性和病毒传播联系起来，表明所有亚基都是干预策略和疫苗开发的潜在靶点。为了在转化性非人灵长类动物模型中确定PC与先天性传播的相关性，我们构建了一种缺乏UL128和UL130直系同源物的恒河猴巨细胞病毒（RhCMV）突变体，该突变体在体外对上皮细胞的感染能力减弱。然而，在妊娠中期早期，用缺乏PC的突变体静脉接种CD4 T细胞耗竭或免疫功能正常的RhCMV血清阴性恒河猴（RM），导致母体RhCMV血浆病毒血症峰值与接种完整PC的RhCMV相似，尽管唾液和尿液中的病毒脱落有限。用完整PC的病毒感染可诱导IgG反应，中和组织培养中RhCMV进入上皮细胞。感染缺乏PC的病毒的动物的这些反应有所降低，但并未完全消失，这些动物也诱导了针对gH的IgG反应。此外，通过检测羊水内的病毒DNA，在感染缺乏PC病毒的多只动物中证实了先天性CMV传播，表明RM中的胎盘传播不依赖于PC。
