Department of Microbiology, The University of Tennessee, Knoxville, Tennessee, USA.
Columbia Center for Translational Immunology, Columbia University, New York City, New York, USA.
mSphere. 2019 Feb 13;4(1):e00586-18. doi: 10.1128/mSphere.00586-18.
Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that can cause severe disease following exposure, during primary infection, or latent virus reactivation in immunocompromised populations. These complications lead to a 1- to 2-billion-dollar economic burden, making vaccine development and/or alternative treatments a high priority. Current treatments for HCMV include nucleoside analogues such as ganciclovir (GCV), foscarnet, and cidofovir. Recently, letermovir, a terminase complex inhibitor, was approved for prophylaxis after stem cell transplantation. These treatments have unwanted side effects, and HCMV is becoming resistant to them. Therefore, we sought to develop an alternative treatment that targets a different stage in viral infection. Currently, small antiviral peptides are being investigated as anti-influenza and anti-HIV treatments. We have developed heparan sulfate-binding peptides as tools for preventing CMV infections. These peptides are highly effective at stopping infection of fibroblasts with derived HCMV and murine cytomegalovirus (MCMV). However, they do not prevent MCMV infection Interestingly, these peptides inhibit infectivity of derived CMVs, albeit not as well as tissue culture-grown CMVs. We further demonstrate that this class of heparan sulfate-binding peptides is incapable of inhibiting MCMV cell-to-cell spread, which is independent of heparan sulfate usage. These data indicate that inhibition of CMV infection can be achieved using synthetic polybasic peptides, but cell-to-cell spread and -grown CMVs require further investigation to design appropriate anti-CMV peptides. In the absence of an effective vaccine to prevent HCMV infections, alternative interventions must be developed. Prevention of viral entry into susceptible cells is an attractive alternative strategy. Here we report that heparan sulfate-binding peptides effectively inhibit entry into fibroblasts of derived CMVs and partially inhibit derived CMVs. This includes the inhibition of urine-derived HCMV (uCMV), which is highly resistant to antibody neutralization. While these antiviral peptides are highly effective at inhibiting cell-free virus, they do not inhibit MCMV cell-to-cell spread. This underscores the need to understand the mechanism of cell-to-cell spread and differences between -derived versus derived CMV entry to effectively prevent CMV's spread.
人巨细胞病毒（HCMV）是一种普遍存在的β疱疹病毒，在初次感染或免疫功能低下人群潜伏病毒再激活时，暴露后可导致严重疾病。这些并发症导致 10 亿至 20 亿美元的经济负担，因此疫苗开发和/或替代疗法成为当务之急。目前治疗 HCMV 的方法包括核苷类似物，如更昔洛韦（GCV）、膦甲酸和缬更昔洛韦。最近，终止酶复合物抑制剂来特莫韦被批准用于干细胞移植后的预防。这些治疗方法有不良反应，并且 HCMV 对它们产生了耐药性。因此，我们试图开发一种针对病毒感染不同阶段的替代疗法。目前，小抗病毒肽作为抗流感和抗 HIV 的治疗方法正在研究中。我们已经开发了硫酸乙酰肝素结合肽作为预防 CMV 感染的工具。这些肽在阻止衍生的 HCMV 和鼠巨细胞病毒（MCMV）感染成纤维细胞方面非常有效。然而，它们并不能预防 MCMV 感染。有趣的是，这些肽抑制衍生 CMVs 的感染性，尽管不如组织培养生长的 CMVs 好。我们进一步证明，这类硫酸乙酰肝素结合肽不能抑制 MCMV 的细胞间传播，这与硫酸乙酰肝素的使用无关。这些数据表明，使用合成多碱性肽可以抑制 CMV 感染，但细胞间传播和组织培养生长的 CMVs 需要进一步研究以设计合适的抗 CMV 肽。在没有有效疫苗预防 HCMV 感染的情况下，必须开发替代干预措施。阻止病毒进入易感细胞是一种有吸引力的替代策略。在这里，我们报告硫酸乙酰肝素结合肽可有效抑制衍生 CMVs 进入成纤维细胞，并部分抑制衍生 CMVs。这包括抑制高度抵抗抗体中和的尿源性 HCMV（uCMV）。虽然这些抗病毒肽在抑制无细胞病毒方面非常有效，但它们不能抑制 MCMV 的细胞间传播。这突显了需要了解细胞间传播的机制以及衍生与衍生 CMV 进入之间的差异，以有效防止 CMV 的传播。
